bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒08‒14
fifteen papers selected by
Ankita Daiya
BITS Pilani
  1. Histone Marks-Dependent Effect on Alternative Splicing: New Perspectives for Targeted Splicing Modulation in Cancer?
  2. The regulation of yes-associated protein/transcriptional coactivator with PDZ-binding motif and their roles in vascular endothelium.
  3. The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition.
  4. A Review of Mathematical and Computational Methods in Cancer Dynamics.
  5. Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.
  6. Single-Circulating Tumor Cell Whole Genome Amplification to Unravel Cancer Heterogeneity and Actionable Biomarkers.
  7. Graph attention network for link prediction of gene regulations from single cell RNA-sequencing data.
  8. Bioinformatics analysis of lncRNAs in the occurrence and development of osteosarcoma.
  9. Deregulated transcription factors and poor clinical outcomes in cancer patients.
  10. CircAGFG1 Promotes Osteosarcoma Progression and Stemness by Competing with miR-302a-3p to Upregulate the Expression of LATS2.
  11. Advances in the Biological Functions and Mechanisms of miRNAs in the Development of Osteosarcoma.
  12. Nitazoxanide inhibits osteosarcoma cells growth and metastasis by suppressing AKT/mTOR and Wnt/β-catenin signaling pathways.
  13. Pan-cancer Landscape of the RUNX Protein Family Reveals their Potential as Carcinogenic Biomarkers and the Mechanisms Underlying their Action.
  14. Hippo-YAP signaling activation and cross talk with PI3K in oral cancer: A retrospective cohort study.
  15. Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner.
  1. Int J Mol Sci. 2022 Jul 27. pii: 8304. [Epub ahead of print]23(15):
    Histone Marks-Dependent Effect on Alternative Splicing: New Perspectives for Targeted Splicing Modulation in Cancer?
    Carol Imbriano, Silvia Belluti.
      Alternative splicing (AS) is a tightly regulated mechanism that generates the complex human proteome from a small number of genes. Cis-regulatory RNA motifs in exons and introns control AS, recruiting positive and negative trans-acting splicing regulators. At a higher level, chromatin affects splicing events. Growing evidence indicates that the popular histone code hypothesis can be extended to RNA-level processes, such as AS. In addition to nucleosome positioning, which can generate transcriptional barriers to shape the final splicing outcome, histone post-translational modifications can contribute to the detailed regulation of single exon inclusion/exclusion. A histone-based system can identify alternatively spliced chromatin stretches, affecting RNAPII elongation locally or recruiting splicing components via adaptor complexes. In tumor cells, several mechanisms trigger misregulated AS events and produce cancer-associated transcripts. On a genome-wide level, aberrant AS can be the consequence of dysfunctional epigenetic splicing code, including altered enrichment in histone post-translational modifications. This review describes the main findings related to the effect of histone modifications and variants on splicing outcome and how a dysfunctional epigenetic splicing code triggers aberrant AS in cancer. In addition, it highlights recent advances in programmable DNA-targeting technologies and their possible application for AS targeted epigenetic modulation.
    Keywords:  alternative splicing; cancer transcript variants; epigenome editing; histone post-translational modifications; histone-code
    DOI:  https://doi.org/10.3390/ijms23158304
  2. Front Cardiovasc Med. 2022 ;9 925254
    The regulation of yes-associated protein/transcriptional coactivator with PDZ-binding motif and their roles in vascular endothelium.
    Wen Zhang, Qian-Qian Li, Han-Yi Gao, Yong-Chun Wang, Min Cheng, Yan-Xia Wang.
      Normal endothelial function plays a pivotal role in maintaining cardiovascular homeostasis, while endothelial dysfunction causes the occurrence and development of cardiovascular diseases. Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) serve as crucial nuclear effectors in the Hippo signaling pathway, which are regulated by mechanical stress, extracellular matrix stiffness, drugs, and other factors. Increasing evidence supports that YAP/TAZ play an important role in the regulation of endothelial-related functions, including oxidative stress, inflammation, and angiogenesis. Herein, we systematically review the factors affecting YAP/TAZ, downstream target genes regulated by YAP/TAZ and the roles of YAP/TAZ in regulating endothelial functions, in order to provide novel potential targets and effective approaches to prevent and treat cardiovascular diseases.
    Keywords:  YAP/TAZ; angiogenesis; endothelial cells; inflammation; oxidative stress
    DOI:  https://doi.org/10.3389/fcvm.2022.925254
  3. ChemMedChem. 2022 Aug 11.
    The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition.
    Pascal Furet, Vincent Bordas, Mickaël Le Douget, Bahaa Salem, Yannick Mesrouze, Patricia Imbach-Weese, Holger Sellner, Markus Voegtle, Nicolas Soldermann, Emilie Chapeau, Markus Wartmann, Clemens Scheufler, Cesar Fernandez, Joerg Kallen, Vito Guagnano, Patrick Chène, Tobias Schmelzle.
      Inhibition of the YAP-TEAD protein protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug-like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP-TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure-based design.
    Keywords:  PPI inhibitors; TEAD; Virtual Screening; YAP; structure-based design
    DOI:  https://doi.org/10.1002/cmdc.202200303
  4. Front Oncol. 2022 ;12 850731
    A Review of Mathematical and Computational Methods in Cancer Dynamics.
    Abicumaran Uthamacumaran, Hector Zenil.
      Cancers are complex adaptive diseases regulated by the nonlinear feedback systems between genetic instabilities, environmental signals, cellular protein flows, and gene regulatory networks. Understanding the cybernetics of cancer requires the integration of information dynamics across multidimensional spatiotemporal scales, including genetic, transcriptional, metabolic, proteomic, epigenetic, and multi-cellular networks. However, the time-series analysis of these complex networks remains vastly absent in cancer research. With longitudinal screening and time-series analysis of cellular dynamics, universally observed causal patterns pertaining to dynamical systems, may self-organize in the signaling or gene expression state-space of cancer triggering processes. A class of these patterns, strange attractors, may be mathematical biomarkers of cancer progression. The emergence of intracellular chaos and chaotic cell population dynamics remains a new paradigm in systems medicine. As such, chaotic and complex dynamics are discussed as mathematical hallmarks of cancer cell fate dynamics herein. Given the assumption that time-resolved single-cell datasets are made available, a survey of interdisciplinary tools and algorithms from complexity theory, are hereby reviewed to investigate critical phenomena and chaotic dynamics in cancer ecosystems. To conclude, the perspective cultivates an intuition for computational systems oncology in terms of nonlinear dynamics, information theory, inverse problems, and complexity. We highlight the limitations we see in the area of statistical machine learning but the opportunity at combining it with the symbolic computational power offered by the mathematical tools explored.
    Keywords:  algorithms; cancer; complex networks; complexity science; dynamical systems; information theory; inverse problems; systems oncology
    DOI:  https://doi.org/10.3389/fonc.2022.850731
  5. Front Pharmacol. 2022 ;13 935536
    Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.
    Chen Chen, Zehua Wang, Yanru Qin.
      Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.
    Keywords:  cancer metabolism; epigenetics; immunity; novel anti-cancer strategy; oncology
    DOI:  https://doi.org/10.3389/fphar.2022.935536
  6. Int J Mol Sci. 2022 Jul 29. pii: 8386. [Epub ahead of print]23(15):
    Single-Circulating Tumor Cell Whole Genome Amplification to Unravel Cancer Heterogeneity and Actionable Biomarkers.
    Tanzila Khan, Therese M Becker, Joseph W Po, Wei Chua, Yafeng Ma.
      The field of single-cell analysis has advanced rapidly in the last decade and is providing new insights into the characterization of intercellular genetic heterogeneity and complexity, especially in human cancer. In this regard, analyzing single circulating tumor cells (CTCs) is becoming particularly attractive due to the easy access to CTCs from simple blood samples called "liquid biopsies". Analysis of multiple single CTCs has the potential to allow the identification and characterization of cancer heterogeneity to guide best therapy and predict therapeutic response. However, single-CTC analysis is restricted by the low amounts of DNA in a single cell genome. Whole genome amplification (WGA) techniques have emerged as a key step, enabling single-cell downstream molecular analysis. Here, we provide an overview of recent advances in WGA and their applications in the genetic analysis of single CTCs, along with prospective views towards clinical applications. First, we focus on the technical challenges of isolating and recovering single CTCs and then explore different WGA methodologies and recent developments which have been utilized to amplify single cell genomes for further downstream analysis. Lastly, we list a portfolio of CTC studies which employ WGA and single-cell analysis for genetic heterogeneity and biomarker detection.
    Keywords:  cancer biomarker; circulating tumor cell (CTC); liquid biopsy; single-cell analysis; whole genome amplification
    DOI:  https://doi.org/10.3390/ijms23158386
  7. Bioinformatics. 2022 Aug 12. pii: btac559. [Epub ahead of print]
    Graph attention network for link prediction of gene regulations from single cell RNA-sequencing data.
    Guangyi Chen, Zhi-Ping Liu.
      MOTIVATION: Single-cell RNA sequencing (scRNA-seq) data provides unprecedented opportunities to reconstruct gene regulatory networks (GRNs) at fine-grained resolution. Numerous unsupervised or self-supervised models have been proposed to infer GRN from bulk RNA-seq data, but few of them are appropriate for scRNA-seq data under the circumstance of low signal-to-noise ratio and dropout. Fortunately, the surging of TF-DNA binding data (e.g., ChIP-seq) makes supervised GRN inference possible. We regard supervised GRN inference as a graph-based link prediction problem that expects to learn gene low-dimensional vectorized representations to predict potential regulatory interactions.RESULTS: In this paper, we present GENELink to infer latent interactions between transcription factors (TFs) and target genes in GRN using graph attention network. GENELink projects the single-cell gene expression with observed TF-gene pairs to a low-dimensional space. Then, the specific gene representations are learned to serve for downstream similarity measurement or causal inference of pairwise genes by optimizing the embedding space. Compared to eight existing GRN reconstruction methods, GENELink achieves comparable or better performance on seven scRNA-seq datasets with four types of ground-truth networks. We further apply GENELink on scRNA-seq of human breast cancer metastasis and reveal regulatory heterogeneity of Notch and Wnt signaling pathways between primary tumour and lung metastasis. Moreover, the ontology enrichment results of unique lung metastasis GRN indicate that mitochondrial oxidative phosphorylation (OXPHOS) is functionally important during the seeding step of the cancer metastatic cascade, which is validated by pharmacological assays.
    AVAILABILITY AND IMPLEMENTATION: The code and data are available at https://github.com/zpliulab/GENELink.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac559
  8. Transl Pediatr. 2022 Jul;11(7): 1182-1198
    Bioinformatics analysis of lncRNAs in the occurrence and development of osteosarcoma.
    Hua Liu, Chenyu Zong, Jiacheng Sun, Haiyang Li, Guangzhen Qin, Xiaojian Wang, Jianwei Zhu, Yang Yang, Qiang Xue, Xianchen Liu.
      Background: Osteosarcoma (OS) is a disease with high mortality in children and adolescents, and metastasis is one of its important clinical features. However, the molecular mechanism of OS occurrence is not completely clear. Thus, we screened potential biomarkers of OS and analyze their prognostic value.Methods: The Cancer Genome Atlas (TCGA) datasets were used to analyze the differential lncRNAs in patients with OS of different immune score and the lncRNAs expressed by immune cells. Cox regression was used to develop the prognosis prediction model and specify the prognosis outcomes. Risk-proportional regression model was constructed, and the samples were divided into high and low groups based on the risk scores for the survival analysis. The areas under the receiver operating characteristic (ROC) curve were calculated and the risk-score model was verified. Finally, using 4 gene sets (comprising chemokines, immune checkpoint blockades, immune activity-related genes, and immune cells), and 4 analysis tools (CIBERSORT, TIMER, XCELL and MCP) to evaluated tumor immune infiltration.
    Results: Twenty-nine long non-coding ribonucleic acids (lncRNAs) were obtained from the intersection of the screened lncRNAs. Caspase recruitment domain-containing protein 8-antisense RNA 1 (CARD8-AS1), lncRNA five prime to Xist (FTX), KAT8 regulatory NSL complex unit 1-antisense RNA 1 (KANSL1-AS1), Neuroplastin Intronic Transcript 1 (NPTN-IT1), oligodendrocyte maturation-associated long intervening non-coding RNA (OLMALINC) and RPARP Antisense RNA 1 (RPARP-AS1) were found to be correlated with survival. Univariate and multivariate regression analysis showed risk score [HR (hazard ratio) 3.5, P value 0.0043; HR 3.7, P value 0.0033] and metastasis (HR 4.7, P value 6.60E-05; HR 4.8, P value 8.36E-05) were the key factors of patients with OS. The areas under curves (AUCs) of the 1-, 3-, and 5-year ROC curves of the prognostic model were 0.715, 0.729, and 0.771. The low-risk patients tended to have a high abundance of immune cells.
    Conclusions: This study showed that a risk score based on 6 lncRNAs has potential value in the prognosis of OS, and patients with low-risk scores have high immune cell infiltration and good prognosis. This study may enrich understandings of underlying mechanisms related to the occurrence and development of OS.
    Keywords:  Osteosarcoma (OS); biomarker; lncRNA; prognosis
    DOI:  https://doi.org/10.21037/tp-22-253
  9. Semin Cancer Biol. 2022 Aug 05. pii: S1044-579X(22)00181-X. [Epub ahead of print]
    Deregulated transcription factors and poor clinical outcomes in cancer patients.
    Yiwei Li, Asfar S Azmi, Ramzi M Mohammad.
      Transcription factors are a group of proteins, which possess DNA-binding domains, bind to DNA strands of promoters or enhancers, and initiate transcription of genes with cooperation of RNA polymerase and other co-factors. They play crucial roles in regulating transcription during embryogenesis and development. Their physiological status in different cell types is also important to maintain cellular homeostasis. Therefore, any deregulation of transcription factors will lead to the development of cancer cells and tumor progression. Based on their functions in cancer cells, transcription factors could be either oncogenic or tumor suppressive. Furthermore, transcription factors have been shown to modulate cancer stem cells, epithelial-mesenchymal transition (EMT) and drug response; therefore, measuring deregulated transcription factors is hypothesized to predict treatment outcomes of patients with cancers and targeting deregulated transcription factors could be an encouraging strategy for cancer therapy. Here, we summarize the current knowledge of major deregulated transcription factors and their effects on causing poor clinical outcome of patients with cancer. The information presented here will help to predict the prognosis and drug response and to design novel drugs and therapeutic strategies for the treatment of cancers by targeting deregulated transcription factors.
    Keywords:  EMT; Transcription factor; cancer stem cell; clinical outcome; drug resistance
    DOI:  https://doi.org/10.1016/j.semcancer.2022.08.001
  10. Evid Based Complement Alternat Med. 2022 ;2022 6370766
    CircAGFG1 Promotes Osteosarcoma Progression and Stemness by Competing with miR-302a-3p to Upregulate the Expression of LATS2.
    Tongchun Li, Guangjie Xing, Liangliang Lu, Xiangzhen Kong, Jinwei Guo.
      This study aimed to investigate the effect of circRNA (circAGFG1) on the proliferation, migration, invasion, and cell stemness of osteosarcoma cells by targeting miR-302a to regulate LATS2. The expression of circAGFG1 in osteosarcoma cells and normal osteoblasts was detected by real-time fluorescent quantitative PCR (RT-qPCR). Cell proliferation, clone formation, and invasion were detected by CCK-8, clone formation, and cell invasion assays. In vivo tumor formation assay was used to detect the effect of circAGFG1 on tumor growth. The expression level of circAGFG1 was upregulated in osteosarcoma cells. The downregulation of circAGFG1 inhibited the proliferation, invasion, and migration of osteosarcoma cells. The overexpression of circAGFG1 enhanced the stemness of osteosarcoma cells. CircAGFG1 was specifically bound to miR-302a to regulate the expression activity of miR-302a. MiR-302a specifically bound to the 3'UTR of LATS2 and inhibited the expression of LATS2. The overexpression of miR-302a reversed the effect of circAGFG1 on the proliferation, invasion, and migration of osteosarcoma cells. CircAGFG1 regulated the expression of LATS2 by miR-302a, thereby regulating the proliferation, migration, and invasion of osteosarcoma cells.
    DOI:  https://doi.org/10.1155/2022/6370766
  11. Technol Cancer Res Treat. 2022 Jan-Dec;21:21 15330338221117386
    Advances in the Biological Functions and Mechanisms of miRNAs in the Development of Osteosarcoma.
    Zihe Dong, Zhipeng Liao, Yonglin He, Chengye Wu, Zixiang Meng, Baolong Qin, Ge Xu, Zeyang Li, Tianxin Sun, Yuyan Wen, Guangjie Li.
      Osteosarcoma is one of the most common primary malignant bone tumors, mainly occurring in children and adolescents, and is characterized by high morbidity and poor prognosis. MicroRNAs, a class of noncoding RNAs consisting of 19 to 25 nucleotides, are involved in cell proliferation, invasion, metastasis, and apoptosis to regulate the development and progression of osteosarcoma. Studies have found that microRNAs are closely related to the diagnosis, treatment, and prognosis of osteosarcoma patients and have an important role in improving drug resistance in osteosarcoma. This paper reviews the role of microRNAs in the pathogenesis of osteosarcoma and their clinical value, aiming to provide a new research direction for diagnosing and treating osteosarcoma and achieving a better prognosis.
    Keywords:  biomarkers; microRNAs; molecular mechanisms; osteosarcoma; targeted therapy‌
    DOI:  https://doi.org/10.1177/15330338221117386
  12. Biol Chem. 2022 Aug 10.
    Nitazoxanide inhibits osteosarcoma cells growth and metastasis by suppressing AKT/mTOR and Wnt/β-catenin signaling pathways.
    Caihong Ye, Mengqi Wei, Huakun Huang, Yuping Wang, Lulu Zhang, Chunmei Yang, Yanran Huang, Jinyong Luo.
      Osteosarcoma (OS) is the most prevalent malignant bone tumor with poor prognosis. Developing new drugs for the chemotherapy of OS has been a focal point and a major obstacle of OS treatment. Nitazoxanide (NTZ), a conventional anti-parasitic agent, has got increasingly noticed because of its favorable antitumor potential. Herein, we investigated the effect of NTZ on human OS cells in vitro and in vivo. The results obtained in vitro showed that NTZ inhibited the proliferation, migration and invasion, arrested cell cycle at G1 phase, while induced apoptosis of OS cells. Mechanistically, NTZ suppressed the activity of AKT/mTOR and Wnt/β-catenin signaling pathways of OS cells. Consistent with the results in vitro, orthotopic implantation model of 143B OS cells further confirmed that NTZ inhibited OS cells growth and lung metastasis in vivo. Notably, NTZ caused no apparent damage to normal cells/tissues. In conclusion, NTZ may inhibit tumor growth and metastasis of human OS cells through suppressing AKT/mTOR and Wnt/β-catenin signaling pathways.
    Keywords:  apoptosis; metastasis; osteosarcoma; proliferation; signaling pathways
    DOI:  https://doi.org/10.1515/hsz-2022-0148
  13. J Transl Int Med. 2022 Jun;10(2): 156-174
    Pan-cancer Landscape of the RUNX Protein Family Reveals their Potential as Carcinogenic Biomarkers and the Mechanisms Underlying their Action.
    Shen Pan, Siyu Sun, Bitian Liu, Yang Hou.
      Background: The RUNX family of transcription factors plays an important regulatory role in tumor development. Although the importance of RUNX in certain cancer types is well known, the pan-cancer landscape remains unclear.Materials and Methods: Data from The Cancer Genome Atlas (TCGA) provides a pan-cancer overview of the RUNX genes. Hence, herein, we performed a pan-cancer analysis of abnormal RUNX expression and deciphered the potential regulatory mechanism. Specifically, we used TCGA multi-omics data combined with multiple online tools to analyze transcripts, genetic alterations, DNA methylation, clinical prognoses, miRNA networks, and potential target genes.
    Results: RUNX genes are consistently overexpressed in esophageal, gastric, pancreatic, and pan-renal cancers. The total protein expression of RUNX1 in lung adenocarcinoma, kidney renal clear cell carcinoma (KIRC), and uterine corpus endometrial carcinoma (UCEC) is consistent with the mRNA expression results. Moreover, increased phosphorylation on the T14 and T18 residues of RUNX1 may represent potential pathogenic factors. The RUNX genes are significantly associated with survival in pan-renal cancer, brain lower-grade glioma, and uveal melanoma. Meanwhile, various mutations and posttranscriptional changes, including the RUNX1 D96 mutation in invasive breast carcinoma, the co-occurrence of RUNX gene mutations in UCEC, and methylation changes in the RUNX2 promoter in KIRC, may be associated with cancer development. Finally, analysis of epigenetic regulator co-expression, miRNA networks, and target genes revealed the carcinogenicity, abnormal expression, and direct regulation of RUNX genes.
    Conclusions: We successfully analyzed the pan-cancer abnormal expression and prognostic value of RUNX genes, thereby providing potential biomarkers for various cancers. Further, mutations revealed via genetic alteration analysis may serve as a basis for personalized patient therapies.
    Keywords:  RUNX family; The Cancer Genome Atlas; pan-cancer analysis; prognosis; regulatory mechanism
    DOI:  https://doi.org/10.2478/jtim-2022-0013
  14. Oral Dis. 2022 Aug 11.
    Hippo-YAP signaling activation and cross talk with PI3K in oral cancer: A retrospective cohort study.
    Juan P Rodrigo, Tania Rodríguez-Santamarta, Daniela Corte, Vanessa García-de-la-Fuente, Nerea Rodríguez-Torres, Paloma Lequerica-Fernández, Corina Lorz, Juana M García-Pedrero, Juan C de Vicente.
      OBJECTIVES: This study aimed to investigate the clinical and prognostic relevance of the Hippo-YAP transactivators YAP1 and TAZ in oral squamous cell carcinoma, and their possible relationship with PI3K/mTOR pathway activation.MATERIALS AND METHODS: Immunohistochemical analysis of YAP1, TAZ, PIK3CA (p110α), p-AKT (Ser473) and p-S6 (Ser235) was performed in paraffin-embedded tissue specimens from 165 OSCC patients. Correlations between protein expression and clinical data were further assessed.
    RESULTS: YAP1 expression was detected in both cytoplasm and nucleus of tumor cells, whereas TAZ expression was only found in the nucleus. Nuclear YAP1 was significantly associated with tumor size (p=.03), neck lymph node metastasis (p=.02), TNM stage (p=.02), and poor differentiation (p=.04). Nuclear TAZ was associated with tobacco (p=.03) and alcohol consumption (p=.04), and poor tumor differentiation (p=.04). There was a positive significant correlation between nuclear and cytoplasmic YAP1, nuclear TAZ, p110α expression, and mTORC1 activation pS6 (S235). Combined expression of nuclear and cytoplasmic YAP1 was prognostic in both univariate and multivariate analyses. Active nuclear YAP1 was significantly and independently associated with poor disease-specific (p=.005, HR = 2.520; 95%CI = 1.319 - 4.816) and overall survival (p=.015, HR = 2.126; 95%CI = 1.155 - 3.916).
    CONCLUSION: Nuclear YAP1 is an independent predictor of poor survival in oral squamous cell carcinoma.
    Keywords:  Hippo-YAP pathway; PIK3CA; TAZ; YAP1; oral squamous cell carcinoma; prognosis
    DOI:  https://doi.org/10.1111/odi.14350
  15. Cell Death Dis. 2022 Aug 08. 13(8): 692
    Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner.
    Lucía García-Gutiérrez, Emma Fallahi, Nourhan Aboud, Niall Quinn, David Matallanas.
      Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified the Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the antiapoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of apoptotic regulators that bind to SMAC and LATS1. Mechanistic analysis shows that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results in apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the proapoptotic signal mediated by the LATS1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes the formation of this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant, which requires C-IAP1 inhibition and the degradation of XIAP, suggesting that the MST2 pathway is part of the mechanism of action of Birinapant. Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway.
    DOI:  https://doi.org/10.1038/s41419-022-05147-3
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