bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–11–27
24 papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Cancer Epigenetics: An Overview.
  2. Evaluation of single-cell RNA-seq clustering algorithms on cancer tumor datasets.
  3. Study of Drug Resistance in Chemotherapy Induced by Extracellular Vesicles on a Microchip.
  4. RUNX Proteins as Epigenetic Modulators in Cancer.
  5. Pan-Cancer Analysis Identifies MNX1 and Associated Antisense Transcripts as Biomarkers for Cancer.
  6. Rapid Single-Pot Assembly of Modular Chromatin Proteins for Epigenetic Engineering.
  7. MAGE-I proteins and cancer-pathways: A bidirectional relationship.
  8. A Pan-Cancer Atlas of Differentially Interacting Hallmarks of Cancer Proteins.
  9. SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer.
  10. Epigenetic regulation of gastrointestinal cancers mediated by long non-coding RNA.
  11. EZH2 deregulates BMP, Hedgehog, and Hippo cell signaling pathways in esophageal squamous cell carcinoma.
  12. Pituitary tumor transforming gene 1 promotes proliferation and malignant phenotype in osteosarcoma via NF-κB signaling.
  13. The Interaction Between SMAD1 and YAP1 Is Correlated with Increased Resistance of Gastric Cancer Cells to Cisplatin.
  14. Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma.
  15. YAP Activation in Promoting Negative Durotaxis and Acral Melanoma Progression.
  16. TIAM2 promotes proliferation and invasion of osteosarcoma cells by activating the JAK2/STAT3 signaling pathway.
  17. Downregulation of protein kinase C gamma reduces epithelial property and enhances malignant phenotypes in colorectal cancer cells.
  18. De novo methylation of histone H3K23 by the methyltransferases EHMT1/GLP and EHMT2/G9a.
  19. Exosomes released from cisplatin-resistant ovarian cancer cells modulate the reprogramming of cells in tumor microenvironments toward the cancerous cells.
  20. Protein interactions: anything new?
  21. The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review.
  22. Identification of genes contributing to cisplatin resistance in osteosarcoma cells.
  23. Pan-cancer analysis of trophinin-associated protein with potential implications in clinical significance, prognosis, and tumor microenvironment in human cancers.
  24. Chromatin as self-returning walks: From population to single cell and back.
  1. Arch Med Res. 2022 Nov 18. pii: S0188-4409(22)00142-4. [Epub ahead of print]
    Cancer Epigenetics: An Overview.
    Félix Recillas-Targa.
      Cancer is a complex disease caused by genetic and epigenetic alterations in the control of cell division. Findings from the field of cancer genomics and epigenomics have increased our understanding of the origin and evolution of tumorigenic processes, greatly advancing our knowledge of the molecular etiology of cancer. Consequently, any contemporary view of cancer research must consider tumorigenesis as a cellular phenomenon that is a result of the interplay between genetic and epigenetic mutations and their interaction with environmental factors, including our microbiome, that influences cellular metabolism and proliferation rates. The integration and better knowledge of these processes will help us to improve diagnosis, prognosis, and future genetic and epigenetic therapies. Here, I present an overview of the epigenetic processes that are affected in cancer and how they contribute to the onset and progression of the disease. Finally, I discuss how the development of sophisticated experimental approaches and computational tools, including novel ways to exploit large data sets, could contribute to the better understanding and treatment of cancer.
    Keywords:  Bioinformatics; Cancer; Chromatin; DNA methylation; Epigenetics; Metabolism; Microbiome
    DOI:  https://doi.org/10.1016/j.arcmed.2022.11.003
  2. Comput Struct Biotechnol J. 2022 ;20 6375-6387
    Evaluation of single-cell RNA-seq clustering algorithms on cancer tumor datasets.
    Alaina Mahalanabis, Andrei L Turinsky, Mia Husić, Erik Christensen, Ping Luo, Alaine Naidas, Michael Brudno, Trevor Pugh, Arun K Ramani, Parisa Shooshtari.
      Tumors are complex biological entities that comprise cell types of different origins, with different mutational profiles and different patterns of transcriptional dysregulation. The exploration of data related to cancer biology requires careful analytical methods to reflect the heterogeneity of cell populations in cancer samples. Single-cell techniques are now able to capture the transcriptional profiles of individual cells. However, the complexity of RNA-seq data, especially in cancer samples, makes it challenging to cluster single-cell profiles into groups that reflect the underlying cell types. We have developed a framework for a systematic examination of single-cell RNA-seq clustering algorithms for cancer data, which uses a range of well-established metrics to generate a unified quality score and algorithm ranking. To demonstrate this framework, we examined clustering performance of 15 different single-cell RNA-seq clustering algorithms on eight different cancer datasets. Our results suggest that the single-cell RNA-seq clustering algorithms fall into distinct groups by performance, with the highest clustering quality on non-malignant cells achieved by three algorithms: Seurat, bigSCale and Cell Ranger. However, for malignant cells, two additional algorithms often reach a better performance, namely Monocle and SC3. Their ability to detect known rare cell types was also among the best, along with Seurat. Our approach and results can be used by a broad audience of practitioners who analyze single-cell transcriptomic data in cancer research.
    Keywords:  Automated algorithms; Cancer; Clustering; Framework; Single-Cell RNA-seq
    DOI:  https://doi.org/10.1016/j.csbj.2022.10.029
  3. Anal Chem. 2022 Nov 24.
    Study of Drug Resistance in Chemotherapy Induced by Extracellular Vesicles on a Microchip.
    Tianyuan Fang, Wei Lu, Jingfeng Zhang, Ke Ge, Zhanhong Chen, Min Wang, Bo Yao.
      Drug resistance in chemotherapy has been greatly challenging for cancer treatment. Research has revealed that extracellular vesicles (EVs) secreted by drug-resistant cells could induce chemoresistance in susceptible cells. However, there are few ways to give direct evidence of it. Herein, we have proposed a microchip-based system to study the drug resistance of a wild-type human lung adenocarcinoma cell line (A549/WT) induced by EVs derived from A549/DDP cells that are resistant to cisplatin (DDP) inherently. EVs derived from A549/DDP were proved to be the crucial factor that enhanced the resistance of A549/WT to DDP through live and dead cell staining, cell viability testing, and immunofluorescence of P-glycoprotein in the off-chip assay. Then, it was further validated that drug resistance of A549/WT cells to DDP significantly increased after being cocultured with A549/DDP cells within 96 h in the on-chip assay. These findings proved that the change of A549/WT drug resistance was caused by intercellular interaction, which was mainly mediated by EVs. In addition, we successfully reversed the EV-induced drug resistance of A549/WT cells by combining DDP and metformin, a hypoglycemic drug with low cytotoxicity when used alone. This microchip system provides a novel tool that has great potential for the investigation of cell interaction, drug resistance, and the tumor microenvironment in fundamental and clinical medicine.
    DOI:  https://doi.org/10.1021/acs.analchem.2c04330
  4. Cells. 2022 Nov 20. pii: 3687. [Epub ahead of print]11(22):
    RUNX Proteins as Epigenetic Modulators in Cancer.
    Hongyang Yi, Yuhao He, Qionghua Zhu, Liang Fang.
      RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis by cross-talking with different signaling pathways such as Wnt, TGF-β, and Hippo. Molecularly, they could serve as transcription factors (TFs) to activate their direct target genes or interact with many other TFs to modulate chromatin architecture globally. Here, we review the current knowledge on the functions and regulations of RUNX proteins in different cancer types and highlight their potential role as epigenetic modulators in cancer.
    Keywords:  RUNX family; cancer; epigenetic modulator; function; regulation
    DOI:  https://doi.org/10.3390/cells11223687
  5. Cells. 2022 Nov 11. pii: 3577. [Epub ahead of print]11(22):
    Pan-Cancer Analysis Identifies MNX1 and Associated Antisense Transcripts as Biomarkers for Cancer.
    Denise Ragusa, Sabrina Tosi, Cristina Sisu.
      The identification of diagnostic and prognostic biomarkers is a major objective in improving clinical outcomes in cancer, which has been facilitated by the availability of high-throughput gene expression data. A growing interest in non-coding genomic regions has identified dysregulation of long non-coding RNAs (lncRNAs) in several malignancies, suggesting a potential use as biomarkers. In this study, we leveraged data from large-scale sequencing projects to uncover the expression patterns of the MNX1 gene and its associated lncRNAs MNX1-AS1 and MNX1-AS2 in solid tumours. Despite many reports describing MNX1 overexpression in several cancers, limited studies exist on MNX1-AS1 and MNX1-AS2 and their potential as biomarkers. By employing clustering methods to visualise multi-gene relationships, we identified a discriminative power of the three genes in distinguishing tumour vs. normal samples in several cancers of the gastrointestinal tract and reproductive systems, as well as in discerning oesophageal and testicular cancer histological subtypes. Notably, the expressions of MNX1 and its antisenses also correlated with clinical features and endpoints, uncovering previously unreported associations. This work highlights the advantages of using combinatory expression patterns of non-coding transcripts of differentially expressed genes as clinical evaluators and identifies MNX1, MNX1-AS1, and MNX1-AS2 expressions as robust candidate biomarkers for clinical applications.
    Keywords:  MNX1; biomarker; cancer cell development; diagnosis; pan-cancer; prognosis; transcription
    DOI:  https://doi.org/10.3390/cells11223577
  6. Methods Mol Biol. 2023 ;2599 191-214
    Rapid Single-Pot Assembly of Modular Chromatin Proteins for Epigenetic Engineering.
    Karmella A Haynes, J Harrison Priode.
      Chromatin is the nucleoprotein complex that organizes genomic DNA in the nuclei of eukaryotic cells. Chromatin-modifying enzymes and chromatin-binding regulators generate chromatin states that affect DNA compaction, repair, gene expression, and ultimately cell phenotype. Many natural chromatin mediators contain subdomains that can be isolated and recombined to build synthetic regulators and probes. Engineered chromatin proteins make up a growing collection of new tools for cell engineering and can help deepen our understanding of the mechanism by which chromatin features, such as modifications of histones and DNA, contribute to the epigenetic states that govern DNA-templated processes. To support efficient exploration of the large combinatorial design space of synthetic chromatin proteins, we have developed a Golden Gate assembly method for one-step construction of protein-encoding recombinant DNA. A set of standard 2-amino acid linkers allows facile assembly of any combination of up to four protein modules, obviating the need to design different compatible overhangs to ligate different modules. Beginning with the identification of protein modules of interest, a synthetic chromatin protein can be built and expressed in vitro or in cells in under 2 weeks.
    Keywords:  Chromatin; Epigenetics; Protein engineering
    DOI:  https://doi.org/10.1007/978-1-0716-2847-8_14
  7. Biochimie. 2022 Nov 17. pii: S0300-9084(22)00292-9. [Epub ahead of print]
    MAGE-I proteins and cancer-pathways: A bidirectional relationship.
    Franco Andrés Pascucci, Micaela Carolina Escalada, Melisa Suberbordes, Candela Vidal, María Fátima Ladelfa, Martín Monte.
      Data emerged from the last 20 years of basic research on tumor antigens positioned the type I MAGE (Melanoma Antigen GEnes - I or MAGE-I) family as cancer driver factors. MAGE-I gene expression is mainly restricted to normal reproductive tissues. However, abnormal re-expression in cancer unbalances the cell status towards enhanced oncogenic activity or reduced tumor suppression. Anomalous MAGE-I gene re-expression in cancer is attributed to altered epigenetic-mediated chromatin silencing. Still, emerging data indicate that MAGE-I can be regulated at protein level. Results from different laboratories suggest that after its anomalous re-expression, specific MAGE-I proteins can be regulated by well-known signaling pathways or key cellular processes that finally potentiate the cancer cell phenotype. Thus, MAGE-I proteins both regulate and are regulated by cancer-related pathways. Here, we present an updated review highlighting the recent findings on the regulation of MAGE-I by oncogenic pathways and the potential consequences in the tumor cell behavior.
    Keywords:  Cancer-associated signaling pathways; Gene expression; MAGE; Oncogenes
    DOI:  https://doi.org/10.1016/j.biochi.2022.11.005
  8. J Pers Med. 2022 Nov 17. pii: 1919. [Epub ahead of print]12(11):
    A Pan-Cancer Atlas of Differentially Interacting Hallmarks of Cancer Proteins.
    Medi Kori, Gullu Elif Ozdemir, Kazim Yalcin Arga, Raghu Sinha.
      Cancer hallmark genes and proteins orchestrate and drive carcinogenesis to a large extent, therefore, it is important to study these features in different cancer types to understand the process of tumorigenesis and discover measurable indicators. We performed a pan-cancer analysis to map differentially interacting hallmarks of cancer proteins (DIHCP). The TCGA transcriptome data associated with 12 common cancers were analyzed and the differential interactome algorithm was applied to determine DIHCPs and DIHCP-centric modules (i.e., DIHCPs and their interacting partners) that exhibit significant changes in their interaction patterns between the tumor and control phenotypes. The diagnostic and prognostic capabilities of the identified modules were assessed to determine the ability of the modules to function as system biomarkers. In addition, the druggability of the prognostic and diagnostic DIHCPs was investigated. As a result, we found a total of 30 DIHCP-centric modules that showed high diagnostic or prognostic performance in any of the 12 cancer types. Furthermore, from the 16 DIHCP-centric modules examined, 29% of these were druggable. Our study presents candidate systems' biomarkers that may be valuable for understanding the process of tumorigenesis and improving personalized treatment strategies for various cancers, with a focus on their ten hallmark characteristics.
    Keywords:  differential interactome; druggability; hallmarks of cancer; personalized treatments; system biomarkers
    DOI:  https://doi.org/10.3390/jpm12111919
  9. J Biol Chem. 2022 Nov 21. pii: S0021-9258(22)01178-4. [Epub ahead of print] 102735
    SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer.
    Aravinda-Bharathi Ramakrishnan, Peter E Burby, Kavya Adiga, Ken M Cadigan.
      Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes by down-regulating β-catenin protein levels. Here, we find using colony formation and cell growth assays that SOX9 surprisingly promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. In contrast to how it indirectly represses Wnt targets, SOX9 directly co-occupies and activates multiple Wnt-responsive enhancers in CRC cells. Our examination of the binding site grammar of these enhancers shows the presence of TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with the presence or absence of SOX9 binding sites on Wnt-regulated enhancers determining whether they are directly activated or indirectly repressed by SOX9.
    Keywords:  Wnt pathway; Wnt signaling; colorectal cancer; enhancers; gene transcription; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2022.102735
  10. Cancer Biomark. 2022 Oct 28.
    Epigenetic regulation of gastrointestinal cancers mediated by long non-coding RNA.
    Abolfazl Akbari, Somayeh Abbasi, Nasrin Borumandnia, Zahra Shokati Eshkiki, Meghdad Sedaghat, Seidamir Pasha Tabaeian, Amirhossein Faghihi Kashani, Atefeh Talebi.
      Long noncoding RNAs (lncRNAs), as well-known modulator of the epigenetic processes, have been shown to contribute to normal cellular physiological and pathological conditions such as cancer. Through the interaction with epigenetic regulators, an aberrant regulation of gene expression can be resulted due to their dysregulation, which in turn, can be involved in tumorigenesis. In the present study, we reviewed the lncRNAs' function and mechanisms that contributed to aberrant epigenetic regulation, which is directly related to gastrointestinal cancer (GI) development and progression. Findings indicated that epigenetic alterations may involve in tumorigenesis and are valuable biomarkers in case of diagnosing, assessing of risk factors, and predicting of GI cancers. This review summarized the accumulated evidence for biological and clinical application to use lncRNAs in GI cancers, including colorectal, gastric, oral, liver, pancreatic and oesophageal cancer.
    Keywords:  Chemoresistance; epigenetic; gastrointestinal cancer; long non-coding RNA; metastasis
    DOI:  https://doi.org/10.3233/CBM-220142
  11. Adv Med Sci. 2022 Nov 17. pii: S1896-1126(22)00043-8. [Epub ahead of print]68(1): 21-30
    EZH2 deregulates BMP, Hedgehog, and Hippo cell signaling pathways in esophageal squamous cell carcinoma.
    Sepideh Ardalan Khales, Mohammad Mahdi Forghanifard, Mohammad Reza Abbaszadegan, Seyed Ebrahim Hosseini.
       PURPOSE: Cell signaling pathways play central roles in cellular stemness state, and aberrant activation of these cascades is attributed to the severity of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to determine the potential impact of enhancer of zeste homolog 2 (EZH2) gene on different cell signaling pathways including bone morphogenesis protein (BMP), Hedgehog, and Hippo in ESCC, and to illuminate EZH2-mediated gene regulatory networks in this aggressive malignancy.
    MATERIALS AND METHODS: EZH2 silencing was performed in two ESCC lines, KYSE-30 and YM-1, followed by gene expression analysis of BMP, Hedgehog, and Hippo signaling using RT-qPCR. EZH2 enforced expression was induced in both cell lines and gene expression of the pathways was evaluated in parallel. The contribution of EZH2 in epithelial-mesenchymal transition (EMT) and cell migration were also evaluated.
    RESULTS: EZH2 downregulation decreased expression of the vital components of the Hedgehog and Hippo signaling, while EZH2 upregulation significantly increased its levels in both ESCC cell lines. The expression of BMP target genes was either reduced in EZH2-expressing cells or increased in EZH2-silencing cells. Enforced expression of EZH2 stimulated downregulation of epithelial markers and upregulation of mesenchymal markers in KYSE-30 and YM-1 ​cells. Significant downregulation of mesenchymal markers was detected following the silencing of EZH2 in the cells. Knocking down EZH2 decreased migration, while enforced expression of EZH2 increased migration in both ESCC lines.
    CONCLUSIONS: These results may support the promoting role of EZH2 in ESCC tumorigenesis through the recruitment of important cell signaling pathways.
    Keywords:  BMP signaling; EZH2; Esophageal squamous cell carcinoma; Hedgehog signaling; Hippo signaling
    DOI:  https://doi.org/10.1016/j.advms.2022.11.002
  12. J Orthop Sci. 2022 Nov 19. pii: S0949-2658(22)00309-8. [Epub ahead of print]
    Pituitary tumor transforming gene 1 promotes proliferation and malignant phenotype in osteosarcoma via NF-κB signaling.
    Xin Hu, Feng Yang, Haibo Mei.
       BACKGROUND: Pituitary tumor transforming gene (PTTG) is an oncogene reported to be actively promotes tumorigenesis in multiple tumors. Osteosarcoma (OS) is the most common primary osseous sarcoma, however, the functional significance and mechanisms underlying whether and how PTTG1 promotes OS remain largely unknown.
    METHODS: Here, in our study, PTTG1 levels in clinical samples and cell lines were determined by western blotting and immunohistochemistry. The viability and migratory/invasive potential of OS cells were assessed using Cell Counting Kit-8, colony formation, wound healing, and Transwell assays. The effects of PTTG1 on NF-κB signaling pathways were evaluated both in vivo and in vitro.
    RESULTS: An abnormally elevated expression of PTTG1was confirmed in human OS tissues and OS cell lines and PTTG1 levels were positively correlated with OS clinicopathological grade. We further showed that knocking down PTTG1 attenuated the viability and migratory/invasive capacity of OS cells (MG63 and HOS-8603). Additionally, the following key mechanistic principle was revealed: knockdown PTTG1-mediated OS tumorgenesis supression was associated with inactivation of the NF-κB pathway. We confirmed these results by additional nonpharmacological intervention and same conclusions were obtained in the context of opposite functional analyses. Furthermore, we also demonstrated that OS cell lines overexpressed PTTG1 showed increased tumorigenesis in athymic nude mice.
    CONCLUSIONS: To sum up, the present study suggests that PTTG1 is involved in the enhancement of the malignancy and carcinogenesis of OS by regulating NF-κB signaling. Accordingly, PTTG1 likely functions as an oncogene in OS and may represent a potential therapeutic target for this cancer.
    Keywords:  NF-κB signaling; Oncogene; Osteosarcoma; Pituitary tumor transforming gene 1; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.jos.2022.10.020
  13. Appl Biochem Biotechnol. 2022 Nov 24.
    The Interaction Between SMAD1 and YAP1 Is Correlated with Increased Resistance of Gastric Cancer Cells to Cisplatin.
    Wanjing Chen, Jingtao Hu, Yawei He, Liang Yu, Yanwei Liu, Yusheng Cheng, Benli Jia, Xianghua Li, Gang Yu, Yong Wang.
      Drug resistance is a major obstacle leading to treating failure and poor outcome in gastric cancer (GC). This study explores the interaction between SMAD family member 1 (SMAD1) and Yes1-associated transcriptional regulator (YAP1) and their roles in cisplatin (DDP) resistance in GC. Transcriptome analysis predicted that SMAD1 is highly expressed in DDP-resistant cells. Elevated SMAD1 expression was detected in GC tissue and cells, especially in DDP-resistant cells (MKN-45/DDP and AGS/DDP). SMAD1 downregulation in cells decreased 50% inhibition value of DDP, reduced proliferation, migration, and invasion, and promoted cell cycle arrest and apoptosis. A protein-protein interaction network suggested a possible SMAD1 and YAP1 interaction in GC. The SMAD1 and YAP1 interaction was validated by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and luciferase assays. SMAD1 bound to YAP1 and activated its transcription. SMAD1 formed complexes with YAP1 in nucleus, and YAP1 upregulation enhanced SMAD1 activity as well. Upregulation of YAP1 restored the malignant behaviors of GC cells suppressed by SMAD1 silencing. In vivo, SMAD1 silencing suppressed growth and DDP resistance of xenograft tumors in nude mice, and this suppression was blocked by YAP1 overexpression again. In conclusion, this study demonstrates that SMAD1 can interact with YAP1 to enhance the DDP resistance of GC cells.
    Keywords:  Cisplatin resistance; SMAD1, YAP1, Gastric cancer; Xenograft tumors
    DOI:  https://doi.org/10.1007/s12010-022-04253-4
  14. J Clin Transl Hepatol. 2023 Feb 28. 11(1): 231-243
    Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma.
    Gan Du, Ruizhe Yang, Jianguo Qiu, Jie Xia.
      Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.
    Keywords:  DNA repair; Hepatocellular carcinoma; Histone deacetylases
    DOI:  https://doi.org/10.14218/JCTH.2022.00079
  15. Cells. 2022 Nov 09. pii: 3543. [Epub ahead of print]11(22):
    YAP Activation in Promoting Negative Durotaxis and Acral Melanoma Progression.
    Yuxing Huang, Jing Su, Jiayong Liu, Xin Yi, Fang Zhou, Jiaran Zhang, Jiaxiang Wang, Xuan Meng, Lu Si, Congying Wu.
      Directed cell migration towards a softer environment is called negative durotaxis. The mechanism and pathological relevance of negative durotaxis in tumor progression still requires in-depth investigation. Here, we report that YAP promotes the negative durotaxis of melanoma. We uncovered that the RhoA-myosin II pathway may underlie the YAP enhanced negative durotaxis of melanoma cells. Acral melanoma is the most common subtype of melanoma in non-Caucasians and tends to develop in a stress-bearing area. We report that acral melanoma patients exhibit YAP amplification and increased YAP activity. We detected a decreasing stiffness gradient from the tumor to the surrounding area in the acral melanoma microenvironment. We further identified that this stiffness gradient could facilitate the negative durotaxis of melanoma cells. Our study advanced the understanding of mechanical force and YAP in acral melanoma and we proposed negative durotaxis as a new mechanism for melanoma dissemination.
    Keywords:  RhoA-Myosin II; YAP; acral melanoma; negative durotaxis
    DOI:  https://doi.org/10.3390/cells11223543
  16. J Bone Oncol. 2022 Dec;37 100461
    TIAM2 promotes proliferation and invasion of osteosarcoma cells by activating the JAK2/STAT3 signaling pathway.
    Shaohua Cheng, Xinghan Huang, Weichun Guo.
      T-cell lymphoma invasion and metastasis 2 (TIAM2) plays a critical role in the malignancy development of many human cancers. However, the specific regulatory mechanism of TIAM2 in osteosarcoma has not yet been explored. In this study, we investigated how TIAM2 affects the proliferation and invasion of osteosarcoma cells and the underlying molecular mechanism. We performed data mining of publicly available datasets to examine whether the expression of TIAM2 is associated with osteosarcoma. We knocked down the expression of and overexpressed TIAM2 in osteosarcoma cells. The proliferative capacity of cells in each group was determined by the Cell Counting Kit-8 assay. Wound healing and Transwell invasion assays were performed to evaluate the migration and invasion abilities of the TIAM2 knockdown and overexpressed osteosarcoma cells. Determination of the function of TIAM2 in vivo was performed in nude mice. Data mining confirmed that TIAM2 expression is associated with poor prognosis in osteosarcoma. TIAM2 expression levels were significantly higher in osteosarcoma cells, and TIAM2 expression knockdown reduced proliferation and invasion abilities. Animal experiments demonstrated that TIAM2 promotes tumor growth. Additional experiments suggested that TIAM2 was significantly related to the activation of the JAK2/STAT3 pathway, and subsequent mechanistic experiments further confirmed this. Our findings suggest that TIAM2 promotes the proliferation and invasion capacities of osteosarcoma cells by activating the JAK2/STAT3 signaling pathway. TIAM2 may serve as a potential prognostic target for patients with OS.
    Keywords:  Invasion; JAK2/STAT3 signaling pathway; Osteosarcoma; Proliferation; TIAM2
    DOI:  https://doi.org/10.1016/j.jbo.2022.100461
  17. iScience. 2022 Dec 22. 25(12): 105501
    Downregulation of protein kinase C gamma reduces epithelial property and enhances malignant phenotypes in colorectal cancer cells.
    Reiko Satow, Yudai Suzuki, Shinobu Asada, Sae Ota, Masashi Idogawa, Shiori Kubota, Noi Ikeo, Atsuko Yoneda, Kiyoko Fukami.
      Loss of epithelial integrity is associated with colorectal cancer (CRC) aggressiveness. Protein kinase C (PKC) is frequently implicated in human cancers, but the role of PKCγ in CRC remains poorly understood. Here, we show that PKCγ, a conventional PKC, is expressed in normal colonic epithelium, but this is lower in dedifferentiated CRC. PKCγ expression was downregulated by SNAI1 overexpression, and low PKCγ expression was associated with poor prognosis in patients with CRC. Transient or stable knockdown of PKCγ reduced E-cadherin expression in CRC cells. PKCγ knockdown enhanced proliferation, anchorage-independent cell growth, resistance to anti-cancer drugs, and in vivo tumor growth of DLD-1 cells. We have also identified phosphorylation substrates for PKCγ. Among them, ARHGEF18, a RhoA activator that stabilizes cell-cell junctions, was phosphorylated and stabilized by PKCγ. Thus, these results suggest that the downregulation of PKCγ decreases the epithelial property of CRC cells and enhances its malignant phenotypes.
    Keywords:  Cancer; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105501
  18. Epigenetics Chromatin. 2022 Nov 21. 15(1): 36
    De novo methylation of histone H3K23 by the methyltransferases EHMT1/GLP and EHMT2/G9a.
    David A Vinson, Kimberly E Stephens, Robert N O'Meally, Shri Bhat, Blair C R Dancy, Robert N Cole, Srinivasan Yegnasubramanian, Sean D Taverna.
      Epigenetic modifications to histone proteins serve an important role in regulating permissive and repressive chromatin states, but despite the identification of many histone PTMs and their perceived role, the epigenetic writers responsible for generating these chromatin signatures are not fully characterized. Here, we report that the canonical histone H3K9 methyltransferases EHMT1/GLP and EHMT2/G9a are capable of catalyzing methylation of histone H3 lysine 23 (H3K23). Our data show that while both enzymes can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23. We also show that pharmacologic inhibition or genetic ablation of EHMT1/GLP and/or EHMT2/G9a leads to decreased H3K23 methylation in mammalian cells. Taken together, this work identifies H3K23 as a new direct methylation target of EHMT1/GLP and EHMT2/G9a, and highlights the differential activity of these enzymes on H3K23 as a substrate.
    Keywords:  EHMT1; EHMT2; Epigenetics; G9a; GLP; H3K18 methylation; H3K23 methylation; Histone
    DOI:  https://doi.org/10.1186/s13072-022-00468-1
  19. Biomed Pharmacother. 2022 Nov 19. pii: S0753-3322(22)01362-2. [Epub ahead of print]157 113973
    Exosomes released from cisplatin-resistant ovarian cancer cells modulate the reprogramming of cells in tumor microenvironments toward the cancerous cells.
    Gizem Yilmaz, Zehra Tavsan, Elcin Cagatay, Gizem Kursunluoglu, Hulya Ayar Kayali.
      Exosomes released from cancer cells are involved in the reorganization of the tumor microenvironment which is the essential aspect of cancer pathogenesis. The intercommunications between cancer cells and diverse cell types in the microenvironment are accomplished by exosomes in ovarian cancer. Internalization pathway, intracellular fate, and biological functions in recipient cells mediated by exosomes released from cisplatin-resistant A2780cis have been studied. Also, histopathological evaluation of tumor, ovary, liver tissues and lymph nodes in vivo studies have been performed. The recipient cells internalized the exosomes via active uptake mechanisms, as shown by confocal microscopy. However, inhibitor studies and flow cytometry analysis showed that each recipient cell line used different uptake pathways. Also, confocal microscopy imaging indicated that the internalized exosomes trapped in the endosomes or phagosomes were distributed to the different cellular compartments including ER, Golgi, and lysosome. The transfer of exosomal oncogenic cargo into the cells modified the intracellular signaling of recipient cells including invasion and metastasis by Boyden-Chamber assay, proliferation by ATP analysis, epithelial-mesenchymal transition (EMT) markers at protein and mRNA levels by western blotting and real-time PCR, and protein kinases in the phospho-kinase array. This remodeling contributed to the initiation of carcinogenesis in ovarian epithelial and peritoneal mesothelial cells, and the progression of carcinogenesis in ovarian cancer cells. In addition, intraperitoneal tumor model studies show that exosomes released from cisplatin-resistant A2780cis cells may play role in the enlargement of lymph nodes, and tumor formations integrated with the liver, attached to the stomach and in the ovarian tissues.
    Keywords:  Exosome; Exosome uptake mechanism; Intracellular trafficking; Invasion; Ovarian cancer; Protein kinase signaling
    DOI:  https://doi.org/10.1016/j.biopha.2022.113973
  20. Essays Biochem. 2022 Nov 23. pii: EBC20220044. [Epub ahead of print]
    Protein interactions: anything new?
    Susana Barrera-Vilarmau, João M C Teixeira, Monika Fuxreiter.
      How do proteins interact in the cellular environment? Which interactions stabilize liquid-liquid phase separated condensates? Are the concepts, which have been developed for specific protein complexes also applicable to higher-order assemblies? Recent discoveries prompt for a universal framework for protein interactions, which can be applied across the scales of protein communities. Here, we discuss how our views on protein interactions have evolved from rigid structures to conformational ensembles of proteins and discuss the open problems, in particular related to biomolecular condensates. Protein interactions have evolved to follow changes in the cellular environment, which manifests in multiple modes of interactions between the same partners. Such cellular context-dependence requires multiplicity of binding modes (MBM) by sampling multiple minima of the interaction energy landscape. We demonstrate that the energy landscape framework of protein folding can be applied to explain this phenomenon, opening a perspective toward a physics-based, universal model for cellular protein behaviors.
    Keywords:  energy landscape framework; fuzziness; higher-order assembly; liquid-liquid phase separation; protein-protein interactions
    DOI:  https://doi.org/10.1042/EBC20220044
  21. Oncogene. 2022 Nov 25.
    The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review.
    Victoria L Tippett, Luke Tattersall, Norain B Ab Latif, Karan M Shah, Michelle A Lawson, Alison Gartland.
      Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
    DOI:  https://doi.org/10.1038/s41388-022-02529-x
  22. FEBS Open Bio. 2022 Nov 21.
    Identification of genes contributing to cisplatin resistance in osteosarcoma cells.
    Mingzhong Xie, Haoping Dai, Qingwen Gu, Changming Xiao, Haozhong Wang, Yang Lei, Chunxiao Wu, Xuening Li, Birong Lin, Sen Li.
      Osteosarcomas are prevalent in children and young adults and have a high recurrence rate. Cisplatin, doxorubicin, and methotrexate are common adjuvant chemotherapy drugs for treatment of osteosarcoma, but multidrug resistance is a growing problem. Therefore, understanding the molecular mechanisms of chemotherapy resistance in osteosarcoma cells is crucial for developing new therapeutic approaches and ultimately improving the prognosis of osteosarcoma patients. To identify genes associated with cisplatin resistance in osteosarcoma, we screened a large-scale mutant library generated by transfecting human osteosarcoma cells with a piggyBac (PB) transposon-based gene activation vector. Several candidate genes were identified by using Splinkerette-PCR paired with Next Generation Sequencing (SP-PCR-NGS). We created a disease-free survival (DFS) predictor model, which includes ZNF720, REEP3, CNNM2, and CGREF1, using TARGET (Therapeutically Applicable Research to Generate Effective Treatments) datasets. Additionally, the results of our enrichment analysis between the Four_genes_high group and Low_group suggested that these four genes may participate in cisplatin resistance in osteosarcoma through cross talk between various signaling pathways, especially the signaling pathway related to bone formation. These data may help guide future studies into chemotherapy for osteosarcoma.
    Keywords:  Chemotherapy; Cisplatin; Genetic screen; Osteosarcoma; Resistance; piggyBac transposon
    DOI:  https://doi.org/10.1002/2211-5463.13524
  23. Front Oncol. 2022 ;12 971618
    Pan-cancer analysis of trophinin-associated protein with potential implications in clinical significance, prognosis, and tumor microenvironment in human cancers.
    Zhenfen Li, Zhangya Pu, Ziyue Yang, Yuanyuan Zhu, Ying Deng, Ning Li, Fang Peng.
       Background: Trophinin-associated protein (TROAP), a cytoplasmic protein, is essential for microtubule cytoskeleton assembly. Mounting evidence demonstrates the vital role of TROAP in regulating the proliferation and migration of cells, but it is unclear how it contributes to cancer progression.
    Methods: The online portals of GEPIA2, Cancer Cell Line Encyclopedia, UALCAN, Human Protein Atlas, and PrognoScan were used to analyze TROAP expression in various tumors and further evaluate its correlation with prognosis. With Western blot and quantitative real-time PCR analysis, we validated TROAP expression levels in hepatocellular carcinoma (HCC) and colorectal cancer (CRC). Ten pairs of HCC and CRC tissues were selected for immunohistochemistry to determine TROAP expression levels in tumors and adjacent tissues, respectively. TROAP knockdown in CRC and HCC cells to verify its role in malignant phenotypes. The genomic and post-transcriptional alterations of TROAP in tumors were determined using the cBioPortal and SangerBox databases. Also, TISIDB was used to investigate the relationship between TROAP expression and tumor microenvironment(TME) among different cancer types. Moreover, a correlation was found between the expression of TROAP and drug sensitivity using GSCALite and CellMiner databases.
    Results: TROAP expression was significantly upregulated in most cancer types, which is consistent with our validated experimental results in HCC and CRC cells, and immunohistochemistry results. And a poor prognosis was linked to TROAP aberrant expression. Our findings indicated that malignant phenotypes and tumorigenesis induced by TROAP could be due to an activation of the PI3K/Akt/GSK-3β signaling pathway. Furthermore, we found a correlation between TROAP expression and genomic and post-transcriptional alterations in various tumors, including tumor mutation burden, and microsatellite instability. Next, we demonstrated that TROAP expression was associated with the infiltration of immune cells, such as neutrophils and macrophages, and correlated with immunomodulation-related genes in the TME. Additionally, the potential role of TROAP expression in predicting the sensitivity of drugs, including melphalan and chlorambucil, was demonstrated.
    Conclusions: Collectively, these findings indicated a significant correlation between TROAP expression and malignant phenotype, functional mechanism, survival possibility, TME, therapeutic potential, and prediction of drug sensitivity in various cancers. Hence, TROAP is a promising biomarker and therapeutic target for predicting cancer outcomes.
    Keywords:  biomarker; immunological; pan-cancer; prognostic; trophinin-associated protein; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.971618
  24. Biophys Rep (N Y). 2022 Mar 09. 2(1): 100042
    Chromatin as self-returning walks: From population to single cell and back.
    Anne R Shim, Kai Huang, Vadim Backman, Igal Szleifer.
      With a growing understanding of the chromatin structure, many efforts remain focused on bridging the gap between what is suggested by population-averaged data and what is visualized for single cells. A popular approach to traversing these scales is to fit a polymer model to Hi-C contact data. However, Hi-C is an average of millions to billions of cells, and each cell may not contain all population-averaged contacts. Therefore, we employ a novel approach of summing individual chromosome trajectories-determined by our Self-Returning Random Walk model-to create populations of cells. We allow single cells to consist of disparate structures and reproduce a variety of experimentally relevant contact maps. We show that the amount of shared topology between cells, and their mechanism of formation, changes the population-averaged structure. Therefore, we present a modeling technique that, with few constraints and little oversight, can be used to understand which single-cell chromatin structures underlie population-averaged behavior.
    DOI:  https://doi.org/10.1016/j.bpr.2021.100042
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