bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023–11–12
eleven papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. p62 bodies: cytosolic zoning by phase separation.
  2. Alteration of chromatin high-order conformation associated with oxaliplatin resistance acquisition in colorectal cancer cells.
  3. Epigenetic modifications: Key players in cancer heterogeneity and drug resistance.
  4. The Hippo pathway in endometrial cancer: a potential therapeutic target?
  5. Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis.
  6. Secretion of acetylated amino acids by drug-induced cancer cells: perspectives on metabolic-epigenetic alterations.
  7. A quantitative evaluation method utilizing the homology concept to assess the state of chromatin within the nucleus of lung cancer.
  8. YAP Signaling Regulates the Cellular Uptake and Therapeutic Effect of Nanoparticles.
  9. VPS35 promotes gastric cancer progression through integrin/FAK/SRC signalling-mediated IL-6/STAT3 pathway activation in a YAP-dependent manner.
  10. Osteosarcomas with few chromosomal alterations and/or affecting adults are genetically heterogeneous.
  11. Increased histone acetylation is the signature of repressed state on the genes transcribed by RNA polymerase III.
  1. J Biochem. 2023 Nov 08. pii: mvad089. [Epub ahead of print]
    p62 bodies: cytosolic zoning by phase separation.
    Reo Kurusu, Hideaki Morishita, Masaaki Komatsu.
      Cellular zoning or partitioning is critical in preventing macromolecules from random diffusion and in orchestrating the spatiotemporal dynamics of biochemical reactions. Along with membranous organelles, membrane-less organelles contribute to the precise regulation of biochemical reactions inside cells. In response to environmental cues, membrane-less organelles rapidly form through liquid-liquid phase separation, sequester certain proteins and RNAs, mediate specific reactions, and dissociate. Among membrane-less organelles, ubiquitin-positive condensates, namely, p62 bodies, maintain cellular homeostasis through selective autophagy of themselves to contribute to intracellular quality control. p62 bodies also activate the anti-oxidative stress response regulated by the KEAP1-NRF2 system. In this review, we present an overview of recent advancements in cellular and molecular biology related to p62 bodies, highlighting their dynamic nature and functions.
    Keywords:  Autophagy; KEAP1-NRF2 system; intracellular quality control; liquid-liquid phase separation; p62 body
    DOI:  https://doi.org/10.1093/jb/mvad089
  2. Exploration (Beijing). 2023 Aug;3(4): 20220136
    Alteration of chromatin high-order conformation associated with oxaliplatin resistance acquisition in colorectal cancer cells.
    Peilong Li, Xueying Shang, Qinlian Jiao, Qi Mi, Mengqian Zhu, Yidan Ren, Juan Li, Li Li, Jin Liu, Chuanxin Wang, Yi Shi, Yunshan Wang, Lutao Du.
      Oxaliplatin is a first-line chemotherapy drug widely adopted in colorectal cancer (CRC) treatment. However, a large proportion of patients tend to become resistant to oxaliplatin, causing chemotherapy to fail. At present, researches on oxaliplatin resistance mainly focus on the genetic and epigenetic alterations during cancer evolution, while the characteristics of high-order three-dimensional (3D) conformation of genome are yet to be explored. In order to investigate the chromatin conformation alteration during oxaliplatin resistance, we performed multi-omics study by combining DLO Hi-C, ChIP-seq as well as RNA-seq technologies on the established oxaliplatin-resistant cell line HCT116-OxR, as well as the control cell line HCT116. The results indicate that 19.33% of the genome regions have A/B compartments transformation after drug resistance, further analysis of the genes converted by A/B compartments reveals that the acquisition of oxaliplatin resistance in tumor cells is related to the reduction of reactive oxygen species and enhanced metastatic capacity. Our research reveals the spatial chromatin structural difference between CRC cells and oxaliplatin resistant cells based on the DLO Hi-C and other epigenetic omics experiments. More importantly, we provide potential targets for oxaliplatin-resistant cancer treatment and a new way to investigate drug resistance behavior under the perspective of 3D genome alteration.
    Keywords:  3D spatial structure; colorectal cancer; multi‐omics; oxaliplatin resistance
    DOI:  https://doi.org/10.1002/EXP.20220136
  3. Transl Oncol. 2023 Nov 04. pii: S1936-5233(23)00207-3. [Epub ahead of print]39 101821
    Epigenetic modifications: Key players in cancer heterogeneity and drug resistance.
    Hana Q Sadida, Alanoud Abdulla, Sara Al Marzooqi, Sheema Hashem, Muzafar A Macha, Ammira S Al-Shabeeb Akil, Ajaz A Bhat.
      Cancer heterogeneity and drug resistance remain pivotal obstacles in effective cancer treatment and management. One major contributor to these challenges is epigenetic modifications - gene regulation that does not involve changes to the DNA sequence itself but significantly impacts gene expression. As we elucidate these phenomena, we underscore the pivotal role of epigenetic modifications in regulating gene expression, contributing to cellular diversity, and driving adaptive changes that can instigate therapeutic resistance. This review dissects essential epigenetic modifications - DNA methylation, histone modifications, and chromatin remodeling - illustrating their significant yet complex contributions to cancer biology. While these changes offer potential avenues for therapeutic intervention due to their reversible nature, the interplay of epigenetic and genetic changes in cancer cells presents unique challenges that must be addressed to harness their full potential. By critically analyzing the current research landscape, we identify knowledge gaps and propose future research directions, exploring the potential of epigenetic therapies and discussing the obstacles in translating these concepts into effective treatments. This comprehensive review aims to stimulate further research and aid in developing innovative, patient-centered cancer therapies. Understanding the role of epigenetic modifications in cancer heterogeneity and drug resistance is critical for scientific advancement and paves the way towards improving patient outcomes in the fight against this formidable disease.
    Keywords:  Cancer heterogeneity; Chromatin remodeling; DNA methylation; Drug resistance; Epigenetic modifications; Epigenetic therapies; Gene expression regulation; Histone modifications
    DOI:  https://doi.org/10.1016/j.tranon.2023.101821
  4. Front Oncol. 2023 ;13 1273345
    The Hippo pathway in endometrial cancer: a potential therapeutic target?
    Xinyun Shen, Qianqian Li, Yiqing Sun, Lingli Chen, Fengxia Xue, Wenyan Tian, Yingmei Wang.
      Endometrial cancer, one of the most prevalent malignant cancers tumors of the female reproductive tract, has been increasing in incidence and mortality rates around the world. The Hippo pathway, one of the eight traditional human cancer signaling pathways, is an intricate signaling network that regulates cell proliferation, differentiation, and migration as well as restricting organ size in response to a range of intracellular and extracellular signals. Inhibiting the Hippo pathway results in aberrant activation of its downstream core component YAP/TAZ, which can enhance cancer cells' metabolism and maintain their stemness. Additionally, the Hippo pathway can modulate the tumor microenvironment and induce drug resistance, where tumorigenesis and tumor progression occur. However, the Hippo pathway has been little researched in endometrial cancer. Here, we aim to review how the Hippo pathway contributes to the onset, development and the potential treatment of endometrial cancer with the aim of providing new therapeutic targets.
    Keywords:  drug resistance; endometrial cancer (EC); hippo pathway; treatment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1273345
  5. Nat Commun. 2023 Nov 08. 14(1): 7209
    Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis.
    W Dean Pontius, Ellen S Hong, Zachary J Faber, Jeremy Gray, Craig D Peacock, Ian Bayles, Katreya Lovrenert, Diana H Chin, Berkley E Gryder, Cynthia F Bartels, Peter C Scacheri.
      The metastasis-invasion cascade describes the series of steps required for a cancer cell to successfully spread from its primary tumor and ultimately grow within a secondary organ. Despite metastasis being a dynamic, multistep process, most omics studies to date have focused on comparing primary tumors to the metastatic deposits that define end-stage disease. This static approach means we lack information about the genomic and epigenomic changes that occur during the majority of tumor progression. One particularly understudied phase of tumor progression is metastatic colonization, during which cells must adapt to the new microenvironment of the secondary organ. Through temporal profiling of chromatin accessibility and gene expression in vivo, we identify dynamic changes in the epigenome that occur as osteosarcoma tumors form and grow within the lung microenvironment. Furthermore, we show through paired in vivo and in vitro CRISPR drop-out screens and pharmacological validation that the upstream transcription factors represent a class of metastasis-specific dependency genes. While current models depict lung colonization as a discrete step within the metastatic cascade, our study shows it is a defined trajectory through multiple epigenetic states, revealing new therapeutic opportunities undetectable with standard approaches.
    DOI:  https://doi.org/10.1038/s41467-023-42656-x
  6. Epigenomics. 2023 Nov 07.
    Secretion of acetylated amino acids by drug-induced cancer cells: perspectives on metabolic-epigenetic alterations.
    Nilesh Kumar Sharma, Sachin C Sarode, Anjali Bahot, Gopinath Sekar.
      The emerging understanding of the super-complex and heterogeneous nature of tumor is well supported by metabolic reprogramming, leading survival advantages. Metabolic reprogramming contributes to tumor responsiveness and resistance to various antitumor drugs. Among the numerous adaptations made by cancer cells in response to drug-induced perturbations, key metabolic alterations involving amino acids and acetylated derivatives of amino acids have received special attention. Considering these implications discussed, targeting cancer-associated metabolic pathways, particularly those involving acetylated amino acids, emerges as an important avenue in the pursuit of combinatorial anticancer strategies. As a result, the introduction of mimetic acetylated amino acids represents a promising new class of inhibitors that could be used alongside traditional chemotherapy agents.
    Keywords:  acetylation; amino acids; cancer; extracellular; intracellular; metabolic reprogramming
    DOI:  https://doi.org/10.2217/epi-2023-0251
  7. Sci Rep. 2023 Nov 09. 13(1): 19585
    A quantitative evaluation method utilizing the homology concept to assess the state of chromatin within the nucleus of lung cancer.
    Yuhki Yokoyama, Kazuki Kanayama, Kento Iida, Masako Onishi, Tadasuke Nagatomo, Mayu Ito, Sachiko Nagumo, Kunimitsu Kawahara, Eiichi Morii, Kazuaki Nakane, Hirofumi Yamamoto.
      Homology is a mathematical tool to quantify "the contact degree", which can be expressed in terms of Betti numbers. The Betti numbers used in this study consisted of two numbers, b0 (a zero-dimensional Betti number) and b1 (a one-dimensional Betti number). We developed a chromatin homology profile (CHP) method to quantify the chromatin contact degree based on this mathematical tool. Using the CHP method we analyzed the number of holes (surrounded areas = b1 value) formed by the chromatin contact and calculated the maximum value of b1 (b1MAX), the value of b1 exceeding 5 for the first time or Homology Value (HV), and the chromatin density (b1MAX/ns2). We attempted to detect differences in chromatin patterns and differentiate histological types of lung cancer from respiratory cytology using these three features. The HV of cancer cells was significantly lower than that of non-cancerous cells. Furthermore, b1MAX and b1MAX/ns2 showed significant differences between small cell and non-small cell carcinomas and between adenocarcinomas and squamous cell carcinomas, respectively. We quantitatively analyzed the chromatin patterns using homology and showed that the CHP method may be a useful tool for differentiating histological types of lung cancer in respiratory cytology.
    DOI:  https://doi.org/10.1038/s41598-023-46213-w
  8. Adv Sci (Weinh). 2023 Nov 09. e2302965
    YAP Signaling Regulates the Cellular Uptake and Therapeutic Effect of Nanoparticles.
    Marco Cassani, Soraia Fernandes, Jorge Oliver-De La Cruz, Helena Durikova, Jan Vrbsky, Marek Patočka, Veronika Hegrova, Simon Klimovic, Jan Pribyl, Doriana Debellis, Petr Skladal, Francesca Cavalieri, Frank Caruso, Giancarlo Forte.
      Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell-nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple-negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.
    Keywords:  YAP-signaling; bio-nano interactions; cancer treatment; mechanobiology; nanoparticles
    DOI:  https://doi.org/10.1002/advs.202302965
  9. Oncogene. 2023 Nov 11.
    VPS35 promotes gastric cancer progression through integrin/FAK/SRC signalling-mediated IL-6/STAT3 pathway activation in a YAP-dependent manner.
    Qingqing Zhou, Feng Qi, Chenfei Zhou, Jun Ji, Jinling Jiang, Chao Wang, Qianfu Zhao, Yangbing Jin, Junwei Wu, Qu Cai, Hua Tian, Jun Zhang.
      VPS35 is a key subunit of the retromer complex responsible for recognising cytosolic retrieval signals in cargo and is involved in neurodegenerative disease and tumour progression. However, the function and molecular mechanism of VPS35 in gastric cancer (GC) remains largely unknown. Here, we demonstrated that VPS35 was significantly upregulated in GC, which was associated with poor survival. VPS35 promoted GC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, VPS35 activated FAK-SRC kinases through integrin-mediated outside-in signalling, leading to the activation of YAP and subsequent IL-6 expression induction in tumour cells. What's more, combined mass spectrometry analysis of MGC-803 cell and bioinformatic analysis, we found that phosphorylation of VPS35 was enhanced in GC cells, and phosphorylated VPS35 has enhanced interaction with ITGB3. VPS35 interacted with ITGB3 and affected the recycling of ITGB3 in GC cells. Gain- and loss-of-function experiments revealed that VPS35 promoted tumour proliferation and metastasis via the IL-6/STAT3 pathway. Interestingly, we also found that STAT3 directly bound to the VPS35 promoter and increased VPS35 transcription, thereby establishing a positive regulatory feedback loop. In addition, we demonstrated that VPS35 knockdown sensitised GC cells to 5-FU and cisplatin. These findings provide evidence that VPS35 promotes tumour proliferation and metastasis, and highlight the potential of targeting VPS35- and IL-6/STAT3-mediated tumour interactions as promising therapeutic strategies for GC.
    DOI:  https://doi.org/10.1038/s41388-023-02885-2
  10. Lab Invest. 2023 Nov 04. pii: S0023-6837(23)00226-X. [Epub ahead of print] 100283
    Osteosarcomas with few chromosomal alterations and/or affecting adults are genetically heterogeneous.
    Valeria Difilippo, Karim H Saba, Emelie Styring, Linda Magnusson, Jenny Nilsson, Michaela Nathrath, Daniel Baumhoer, Karolin H Nord.
      Osteosarcoma is the most common primary bone malignancy. It is most often detected in children and adolescents and is commonly associated with TP53 alterations along with a high number of chromosomal rearrangements. However, osteosarcoma can affect patients of any age and some tumors display less genetic complexity. Besides TP53 variants, data on key driving mutations is lacking for many osteosarcomas, particularly those affecting adults. To detect osteosarcoma-specific alterations, we screened transcriptomic and genomic sequencing and copy number data from 150 bone tumors originally diagnosed as osteosarcoma. To increase the precision in gene fusion detection, we developed a bioinformatic tool denoted NAFuse, which extracts gene fusions that are verified at both the genomic and transcriptomic levels. Apart from the already reported genetic subgroups of osteosarcoma with TP53 structural variants, or MDM2 and/or CDK4 amplification, we did not identify any recurrent genetic driver that signifies the remaining cases. Among the plethora of mutations identified, we found genetic alterations characteristic for, or similar to, those of other bone and soft tissue tumors in eight cases. These mutations were found in tumors with relatively few other genetic alterations and/or affecting adults. Due to lack of clinical context and available tissue, we can question the diagnosis only on a genetic basis. Our findings, however, support the notion that osteosarcomas with few chromosomal alterations and/or affecting adults seem genetically distinct from conventional osteosarcomas of children and adolescents.
    Keywords:  NAFuse; bone tumor; gene fusion; osteosarcoma; sarcoma; soft tissue tumor
    DOI:  https://doi.org/10.1016/j.labinv.2023.100283
  11. Gene. 2023 Nov 03. pii: S0378-1119(23)00799-0. [Epub ahead of print]893 147958
    Increased histone acetylation is the signature of repressed state on the genes transcribed by RNA polymerase III.
    Aneeshkumar Gopalakrishnan Arimbasseri, Ashutosh Shukla, Ashis Kumar Pradhan, Purnima Bhargava.
      Several covalent modifications are found associated with the transcriptionally active chromatin regions constituted by the genes transcribed by RNA polymerase (pol) II. Pol III-transcribed genes code for the small, stable RNA species, which participate in many cellular processes, essential for survival. Pol III transcription is repressed under most of the stress conditions by its negative regulator Maf1. We found that most of the histone acetylations increase with starvation-induced repression on several genes transcribed by the yeast pol III. On one of these genes, SNR6 (coding for the U6snRNA), a strongly positioned nucleosome in the gene upstream region plays regulatory role under repression. On this nucleosome, the changes in H3K9 and H3K14 acetylations show different dynamics. During repression, acetylation levels on H3K9 show steady increase whereas H3K14 acetylation increases with a peak at 40 min after which levels reduce. Both the levels settle by 2 hr to a level higher than the active state, which revert to normal levels with nutrient repletion. The increase in H3 acetylations is seen in the mutants reported to show reduced SNR6 transcription but not in the maf1Δ cells. This increase on a regulatory nucleosome may be part of the signaling mechanisms, which prepare cells for the stress-related quick repression as well as reactivation. The contrasting association of the histone acetylations with pol II and pol III transcription may be an important consideration to make in research studies focused on drug developments targeting histone modifications.
    Keywords:  Acetylations; Gcn5; H3K14; H3K9; H4K16; Pol III; Repression; Rpd3; SNR6; Transcription; U6 snRNA
    DOI:  https://doi.org/10.1016/j.gene.2023.147958
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