bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–11–17
eleven papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Molecular dynamics simulations of a multicellular model with cell-cell interactions and Hippo signaling pathway.
  2. Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.
  3. Role of reactive oxygen species in regulating epigenetic modifications.
  4. Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.
  5. Prognostic signature and immunotherapeutic relevance of Focal adhesion signaling pathway-related genes in osteosarcoma.
  6. Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.
  7. Follow the CSF flow: probing multiciliated ependymal cells in brain pathology.
  8. SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling.
  9. Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer.
  10. High BRAF V600 Mutation Level Associated with Worse Outcome in Metastatic Melanoma Patients Receiving BRAF and MEK Inhibitors.
  11. P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress.
  1. PLoS Comput Biol. 2024 Nov;20(11): e1012536
    Molecular dynamics simulations of a multicellular model with cell-cell interactions and Hippo signaling pathway.
    Toshihito Umegaki, Hisashi Moriizumi, Fumiko Ogushi, Mutsuhiro Takekawa, Takashi Suzuki.
      The transcriptional coactivator Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) induces cell proliferation through nuclear localization at low cell density. Conversely, at extremely high cell density, the Hippo pathway, which regulates YAP/TAZ, is activated. This activation leads to the translocation of YAP/TAZ into the cytoplasm, resulting in cell cycle arrest. Various cancer cells have several times more YAP/TAZ than normal cells. However, it is not entirely clear whether this several-fold increase in YAP/TAZ alone is sufficient to overcome proliferation inhibition (contact inhibition) under high-density conditions, thereby allowing continuous proliferation. In this study, we construct a three-dimensional (3D) mathematical model of cell proliferation incorporating the Hippo-YAP/TAZ pathway. Herein, a significant innovation in our approach is the introduction of a novel modeling component that inputs cell density, which reflects cell dynamics, into the Hippo pathway and enables the simulation of cell proliferation as the output response. We assume such 3D model with cell-cell interactions by solving reaction and molecular dynamics (MD) equations by applying adhesion and repulsive forces that act between cells and frictional forces acting on each cell. We assume Lennard-Jones (12-6) potential with a softcore character so that each cell secures its exclusive domain. We set cell cycles composed of mitotic and cell growth phases in which cells divide and grow under the influence of cell kinetics. We perform mathematical simulations at various YAP/TAZ levels to investigate the extent of YAP/TAZ increase required for sustained proliferation at high density. The results show that a twofold increase in YAP/TAZ levels of cancer cells was sufficient to evade cell cycle arrest compared to normal cells, enabling cells to continue proliferating even under high-density conditions. Finally, this mathematical model, which incorporates cell-cell interactions and the Hippo-YAP/TAZ pathway, may be applicable for evaluating cancer malignancy based on YAP/TAZ levels, developing drugs to suppress the abnormal proliferation of cancer cells, and determining appropriate drug dosages. The source codes are freely available.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012536
  2. Cancers (Basel). 2024 Oct 25. pii: 3605. [Epub ahead of print]16(21):
    Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.
    Chitra Palanivel, Tabbatha N Somers, Bailey M Gabler, Yuanhong Chen, Yongji Zeng, Jesse L Cox, Parthasarathy Seshacharyulu, Jixin Dong, Ying Yan, Surinder K Batra, Michel M Ouellette.
      Background: Oncogenic mutations in the KRAS gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1T17N mutant. Several E3 ubiquitin ligases, including SCFβTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383-388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases.
    Keywords:  GTPase; Hippo; Rac1; Ras; YAP; pancreatic cancer; ubiquitin ligases; βTrCP
    DOI:  https://doi.org/10.3390/cancers16213605
  3. Cell Signal. 2024 Nov 07. pii: S0898-6568(24)00477-7. [Epub ahead of print]125 111502
    Role of reactive oxygen species in regulating epigenetic modifications.
    Yutong Chen, Ying-Qiang Shen.
      Reactive oxygen species (ROS) originate from diverse sources and regulate multiple signaling pathways within the cellular environment. Their generation is intricately controlled, and disruptions in their signaling or atypical levels can precipitate pathological conditions. Epigenetics, the examination of heritable alterations in gene expression independent of changes in the genetic code, has been implicated in the pathogenesis of various diseases through aberrant epigenetic modifications. The significant contribution of epigenetic modifications to disease progression underscores their potential as crucial therapeutic targets for a wide array of medical conditions. This study begins by providing an overview of ROS and epigenetics, followed by a discussion on the mechanisms of epigenetic modifications such as DNA methylation, histone modification, and RNA modification-mediated regulation. Subsequently, a detailed examination of the interaction between ROS and epigenetic modifications is presented, offering new perspectives and avenues for exploring the mechanisms underlying specific epigenetic diseases and the development of novel therapeutics.
    Keywords:  DNA methylation; Epigenetics; Histone PTMs; Mechanism diseases; RNA modifications; ROS
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111502
  4. ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3573-3584
    Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.
    Venugopal Vangala, Yu-Chi Chen, Saketh S Dinavahi, Krishne Gowda, Nazir A Lone, Meenhard Herlyn, Joseph Drabick, Klaus Helm, Jiyue Zhu, Rogerio I Neves, Arun K Sharma, Arthur Berg, Marco Archetti, Shantu Amin, Todd D Schell, Gavin P Robertson.
      The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDHhigh and ALDHlow subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.
    DOI:  https://doi.org/10.1021/acsptsci.4c00453
  5. Heliyon. 2024 Nov 15. 10(21): e38523
    Prognostic signature and immunotherapeutic relevance of Focal adhesion signaling pathway-related genes in osteosarcoma.
    Zhiqiang Wu, Zhiqing Wang, Zhanqiang Hua, Yingzheng Ji, Qingrong Ye, Hao Zhang, Wangjun Yan.
       Background: As the most common primary malignant bone tumor in children and adolescents, osteosarcoma currently lacks an effective clinical cure. Focal adhesion plays a crucial role in tumor invasion, migration, and drug resistance by mediating communication between the extracellular matrix and tumor cells. This study investigated the prognostic features and immunotherapeutic relevance of focal adhesion pathway-related genes in osteosarcoma to aid in the development of new therapeutic options.
    Methods: We obtained mutational, transcriptomic, gene expression, and clinical data of osteosarcoma patients from the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective (TARGET) databases. Differentially expressed genes were screened, followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Kaplan-Meier survival analysis was performed for genes related to the focal adhesion pathway, and multivariate Cox regression analysis was employed to construct a prognostic signature model. Genes such as SIGLEC15, TIGIT, CD274, HAVCR2, PDCD1, CTLA4, and LAG3 were extracted from the TARGET and CCLE databases for osteosarcoma patients and osteosarcoma cell lines, respectively，to observe the expression of immune checkpoint-related genes. Finally, qRT-PCR was used to verify the expression of these immune checkpoint-related genes in osteosarcoma cell lines.
    Results: In our study, 376 samples were analyzed, including 369 osteosarcoma samples and 7 normal tissue samples. We identified 50 up-regulated and 28 down-regulated differentially expressed genes. Among these, 10 Candidate genes relative to focal Adhesion were selected， and CAV1, ZYX, and ITGA5 were found to have a significant prognostic role based on survival analysis of osteosarcoma samples from the TARGET database. A predictive signature model related to the focal adhesion signaling pathway was constructed using these genes, and the AUCs of the 1-year, 3-year, and 5-year ROC curves were 0. 647, 0. 712, and 0. 717, respectively. The overall survival (OS) rate of osteosarcoma patients with high-risk scores was poorer than those with low-risk scores. Then, samples were divided into two subgroups based on the expression of the three genes, revealing significant differences in the expression of certain immune checkpoint-related genes between the subgroups. Additionally, above three genes and immune checkpoint-related genes in osteosarcoma cell lines were extracted from the CCLE database, showing high expression levels in eight osteosarcoma cell lines. We observed that CD274 and PDCD1LG2 were highly expressed in some osteosarcoma cell lines. Finally, the expression of CAV1, ZYX, ITGA5, CD80, CD274, and PDCD1LG2 in osteosarcoma cell lines was verified by qRT-PCR.
    Conclusions: Our study validated the prognostic role of three focal adhesion pathway-related genes (ZYX, CAV1, and ITGA5) in patients with osteosarcoma and constructed a prognostic signature model associated with the focal adhesion signaling pathway. We identified significant differences in the expression of multiple immune checkpoint-related genes among subgroups defined by the three genes. Additionally, CD274 and PDCD1LG2 showed higher expression in osteosarcoma cell lines characterized by these genes. These findings may aid in the selection of effective immunotherapy for specific osteosarcoma patients.
    Keywords:  CAV1; Focal adhesion; ITGA5; Osteosarcoma; TME; ZYX
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38523
  6. Cell Death Dis. 2024 Nov 08. 15(11): 801
    Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.
    Jaehyun Lee, Chaelin You, Geunho Kwon, Junho Noh, Kyubin Lee, Kyunghwan Kim, Keunsoo Kang, Kyuho Kang.
      Enhancer of zeste homolog 2 (EZH2), a key protein implicated in various cancers including hepatocellular carcinoma (HCC), is recognized for its association with epigenetic dysregulation and pathogenesis. Despite clinical explorations into EZH2-targeting therapies, the mechanisms underlying its role in gene suppression in HCC have remained largely unexplored. Here, we integrate epigenomic and transcriptomic analyses to uncover the transcriptional landscape modulated by selective EZH2 inhibition in HCC. By reanalyzing transcriptomic data of HCC patients, we demonstrate that EZH2 overexpression correlates with poor patient survival. Treatment with the EZH2 inhibitor tazemetostat restored expression of genes involved in cysteine-methionine metabolism and lipid homeostasis, while suppressing angiogenesis and oxidative stress-related genes. Mechanistically, we demonstrate EZH2-mediated H3K27me3 enrichment at cis-regulatory elements of transsulfuration pathway genes, which is reversed upon inhibition, leading to increased chromatin accessibility. Among 16 EZH2-targeted candidate genes, BHMT and CDO1 were notably correlated with poor HCC prognosis. Tazemetostat treatment of HCC cells increased BHMT and CDO1 expression while reducing levels of ferroptosis markers FSP1, NFS1, and SLC7A11. Functionally, EZH2 inhibition dose-dependently reduced cell viability and increased lipid peroxidation in HCC cells. Our findings reveal a novel epigenetic mechanism controlling lipid peroxidation and ferroptosis susceptibility in HCC, providing a rationale for exploring EZH2-targeted therapies in this malignancy.
    DOI:  https://doi.org/10.1038/s41419-024-07198-0
  7. Trends Mol Med. 2024 Nov 07. pii: S1471-4914(24)00274-0. [Epub ahead of print]
    Follow the CSF flow: probing multiciliated ependymal cells in brain pathology.
    Adam M R Groh, Liam Hodgson, Danilo Bzdok, Jo Anne Stratton.
      Multiciliated ependymal cells regulate cerebrospinal fluid (CSF) microcirculation and form a dynamic CSF-brain interface. Emerging evidence suggests that ependymal cells enter reactive states in response to pathology that are associated with ciliary and junctional protein alterations. The drivers of these alterations, likely from both acquired and inherited mechanisms, remain elusive.
    Keywords:  brain border; brain ventricles; cerebrospinal fluid; ependymoglial cells; reactive glia; ventriculomegaly
    DOI:  https://doi.org/10.1016/j.molmed.2024.10.007
  8. Cell Death Dis. 2024 Nov 12. 15(11): 820
    SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling.
    Jiaguan Zhang, Zeshou Gao, Yi Yang, Zhenhao Li, Binjie Wu, Chunxin Fan, Yuyan Zheng, Ruohan Yang, Fangrong Zhang, Xiaohuang Lin, Daoshan Zheng.
      SNF2L encodes an ISWI chromatin remodeling factor that promotes gene transcription and is consistently elevated in cancers. Previous studies have shown that inhibiting SNF2L expression in cancer cells leads to significant growth suppression, DNA damage, and cell death. However, the underlying mechanisms remain poorly understood. In this study, we demonstrated that cancer cells lacking SNF2L show significantly decreased glutathione (GSH) levels, leading to elevated reactive oxygen species (ROS) and increased oxidative stress. SNF2L deficiency also heightened the sensitivity of cancer cells to APR-246, a drug that depletes GSH and induces oxidative stress, consequently decreasing cell viability and increasing ROS levels, regardless of p53 status. Mechanistically, we found that NRF2 recruits SNF2L to the SLC7A11 promoter, leading to increased chromatin accessibility and facilitating SLC7A11 transcription. This results in decreased cystine uptake and impaired GSH biosynthesis. These findings suggest that targeting the SNF2L/SLC7A11 axis could enhance the effectiveness of APR-246 by depleting GSH and increasing ROS level in cancer cells, highlighting SNF2L as a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-024-07221-4
  9. Oncogene. 2024 Nov 08.
    Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer.
    Ming Wen, Yanfang Qiu, Meng Wang, Feiyu Tang, Wenfeng Hu, Yongwei Zhu, Wenchao Zhao, Wenzhen Hu, Zhuohang Chen, Yumei Duan, Anke Geng, Fengbo Tan, Yuqiang Li, Qian Pei, Haiping Pei, Zhiyong Mao, Ningbo Wu, Lunquan Sun, Rong Tan.
      The effectiveness of radiotherapy in colorectal cancer (CRC) relies on its ability to induce cell death via the generation of reactive oxygen species (ROS). However, genes responsible for mitigating oxidative stress can impede radiotherapy's efficacy. In this study, we elucidate a significant association between the nucleolar protein Fibrillarin (FBL) and the oxidative stress response in CRC tumors. Our findings reveal elevated expression of FBL in colorectal cancer, which positively correlates with oxidative stress levels. Mechanistically, FBL demonstrates direct accumulation at DNA damage sites under the regulation of PARP1. Specifically, the N-terminal GAR domain of FBL is susceptible to PARylation by PARP1, enabling FBL to recognize PARylated proteins. The accumulation of damaged FBL plays a pivotal role in facilitating short-patched base excision repair by recruiting Ligase III and disassociating PCNA and FEN1. Moreover, tumors with heightened FBL expression exhibit reduced DNA damage levels but increased sensitivity to combined low-dose radiotherapy and olaparib treatment. This underscores the potential of leveraging PARP inhibitors to augment radiotherapy sensitivity in CRC cases characterized by elevated FBL expression, offering a promising therapeutic avenue.
    DOI:  https://doi.org/10.1038/s41388-024-03207-w
  10. Acta Derm Venereol. 2024 Nov 07. 104 adv40913
    High BRAF V600 Mutation Level Associated with Worse Outcome in Metastatic Melanoma Patients Receiving BRAF and MEK Inhibitors.
    Ariane Fizazi, Chris Serrand, Alexandre Evrard, Blanche Bergeret, Pierre-Emmanuel Stoebner, Myriam Marque.
      The prognostic value of BRAF V600 mutation level on clinical outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and MEK inhibitors remains uncertain. The association was retrospectively analysed between BRAF V600 mutation level (defined as the ratio of the quantification of the BRAF V600 allele to the percentage of tumoral cells in the sample analysed) and progression-free and overall survival (PFS and OS, respectively) and 3-month response rate in a cohort of 58 patients with metastatic melanoma who harboured BRAF V600E/K mutations and received dual targeted-therapy BRAF/MEK inhibitors. The BRAF mutation level cut-off determined by the area under the receiver operating characteristic curve after internal validation by bootstrap methods was 0.44. Risk of poor PFS and OS was associated with BRAF V600 mutation level > 0.44 on multivariate analysis (p = 0.02 and p = 0.02, respectively) after adjusting for major confounding factors (age, sex, lactate dehydrogenase level, brain metastasis, and treatment line). No association was found between BRAF mutation level and 3-month response rate. Our study shows that high BRAF V600 mutation level in melanoma tissue was associated with poor prognosis in patients with metastatic melanoma treated with BRAF and MEK inhibitors.
    DOI:  https://doi.org/10.2340/actadv.v104.40913
  11. Cell Mol Bioeng. 2024 Oct;17(5): 507-523
    P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress.
    Chloe P Whitworth, Wen Y Aw, Elizabeth L Doherty, Chenchen Handler, Yogeshwari Ambekar, Aanya Sawhney, Giuliano Scarcelli, William J Polacheck.
       Purpose: P300 is a lysine acetyltransferase that plays a significant role in regulating transcription and the nuclear acetylome. While P300 has been shown to be required for the transcription of certain early flow responsive genes, relatively little is known about its role in the endothelial response to hemodynamic fluid stress. Here we sought to define the role of P300 in mechanotransduction of fluid shear stress in the vascular endothelium.
    Methods: To characterize cellular mechanotransduction and physical properties after perturbation of P300, we performed bulk RNA sequencing, confocal and Brillouin microscopy, and functional assays on HUVEC.
    Results: Inhibition of P300 in HUVEC triggers a hyper-alignment phenotype, with cells aligning to flow sooner and more uniformly in the presence of the P300 inhibitor A-485 compared to load controls. Bulk transcriptomics revealed differential expression of genes related to the actin cytoskeleton and migration in cells exposed to A-485. Scratch wound and bead sprouting assays demonstrated that treatment with A-485 increased 2D and 3D migration of HUVEC. Closer examination of filamentous actin revealed the presence of a perinuclear actin cap in both P300 knockdown HUVEC and HUVEC treated with A-485. Interrogation of cell mechanical properties via Brillouin microscopy demonstrated that HUVEC treated with A-485 had lower Brillouin shifts in both the cell body and the nucleus, suggesting that P300 inhibition triggers an increase in cellular and nuclear compliance.
    Conclusions: Together, these results point to a novel role of P300 in modulating endothelial cell mechanics and mechanotransduction of hemodynamic shear stress.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00805-2.
    Keywords:  Cell mechanics; Mechanotransduction; Nuclear mechanotransduction; Vascular biology
    DOI:  https://doi.org/10.1007/s12195-024-00805-2
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