bims-ectoca 2022-11-20 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022‒11‒20
eight papers selected by
Ankita Daiya
BITS Pilani

The crosstalk between LINC01089 and hippo pathway inhibits osteosarcoma progression.
Chloroquine induces transitory attenuation of proliferation of human lung cancer cells through regulation of mutant P53 and YAP.
Investigating pathological epigenetic aberrations by epi-proteomics.
Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode.
mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters.
Identification of risk model based on glycolysis-related genes in the metastasis of osteosarcoma.
A lineage tree-based hidden Markov model quantifies cellular heterogeneity and plasticity.
Clonal evolution and expansion associated with therapy resistance and relapse of Colorectal Cancer.

J Bone Miner Metab. 2022 Nov 18.

The crosstalk between LINC01089 and hippo pathway inhibits osteosarcoma progression.

Hao Zhang, Lin Zhou, Shaopu Hu, Wei Gu, Zhiqiang Li, Jun Sun, Xiaoen Wei, Yongjun Wang.

  INTRODUCTION: Osteosarcoma is the most common malignancy in children, with high morbidity worldwide. Researches indicated that long non-coding RNAs (lncRNAs) played crucial roles in various cancers. Nevertheless, study investigating lncRNA long intergenic non-protein coding RNA 1089 (LINC01089) in osteosarcoma is extremely rare. Thus, the research of LINC01089 is of great significance.MATERIALS AND METHODS: qRT-PCR and western blot were done to test the expression of RNAs and proteins in osteosarcoma cells. Functional assays were carried out to evaluate biological behaviors of hFOB1.19 and osteosarcoma cells with or without LINC01089 knockdown and overexpression. In vitro and in vivo experiments in a rescue manner were performed to reveal the influences of LINC01089 and Hippo pathway on osteosarcoma cell phenotype and tumor growth.
RESULTS: LINC01089 was down-regulated in osteosarcoma cells and overexpressing LINC01089 was validated to restrain cell growth in vitro and tumor growth in vivo. Additionally, silencing LINC01089 could exacerbate cell malignant behaviors. Correlation of LINC01089 and Hippo pathway was proved. Overexpressing LINC01089 could activate Hippo pathway to exert antitumor effects.
CONCLUSION: LINC01089 could restrain the progression of osteosarcoma through activating Hippo pathway.

Keywords:  Biological functions; Hippo pathway; LINC01089; Osteosarcoma

DOI:  https://doi.org/10.1007/s00774-022-01377-9
Mol Biol Rep. 2022 Nov 16.

Chloroquine induces transitory attenuation of proliferation of human lung cancer cells through regulation of mutant P53 and YAP.

Heena Saini, Mahima Choudhary, Harshita Sharma, Shibasish Chowdhury, Sudeshna Mukherjee, Rajdeep Chowdhury.

  BACKGROUND: Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer-associated deaths worldwide. Though recent development in targeted therapy has improved NSCLC prognosis, yet there is an unmet need to identify novel causative factors and appropriate therapeutic regimen against NSCLCs.METHODS AND RESULTS: In this study, we identify key molecular factors de-regulated in NSCLCs. Analyze their expression by real-time PCR and immunoblot; map their localization by immuno-fluorescence microscopy. We further propose an FDA approved drug, chloroquine (CQ) that affects the function of the molecular factors and hence can be repurposed as a therapeutic strategy against NSCLCs. Available NSCLC mutation data reflects a high probabilistic chance of patients harboring a p53 mutation, especially a gain of function (GOF)-R273H mutation. The GOF-P53 mutation enables the P53 protein to potentially interact with non-canonical protein partners facilitating oncogenesis. In this context, analysis of existing transcriptomic data from R273H-P53 expressing cells shows a concomitant up-regulation of Yes-associated protein (YAP) transcriptional targets and its protein partner TEAD1 in NSCLCs, suggesting a possible link between R273H-P53 and YAP. We therefore explored the inter-dependence of R273H-P53 and YAP in NSCLC cells. They were found to co-operatively regulate NSCLC proliferation. Genetic or pharmacological inhibition of YAP and GOF-P53 resulted in sensitization of NSCLC cells. Further analysis of pathways controlled by GOF-P53 and YAP showed that they positively regulate the cellular homeostatic process- autophagy to mediate survival. We hence postulated that a modulation of autophagy might be a potent strategy to curb proliferation. In accordance to above, autophagy inhibition, especially with the FDA-approved drug- chloroquine (CQ) resulted in cytoplasmic accumulation and reduced transcriptional activity of GOF-P53 and YAP, leading to growth arrest of NSCLC cells.
CONCLUSION: Our study highlights the importance of GOF-P53 and YAP in NSCLC proliferation and proposes autophagy inhibition as an efficient strategy to attenuate NSCLC tumorigenesis.

Keywords:  Autophagy; Chloroquine; NSCLC; R273H-P53; YAP

DOI:  https://doi.org/10.1007/s11033-022-08072-y
Clin Epigenetics. 2022 Nov 12. 14(1): 145

Investigating pathological epigenetic aberrations by epi-proteomics.

Giulia Robusti, Alessandro Vai, Tiziana Bonaldi, Roberta Noberini.

  Epigenetics includes a complex set of processes that alter gene activity without modifying the DNA sequence, which ultimately determines how the genetic information common to all the cells of an organism is used to generate different cell types. Dysregulation in the deposition and maintenance of epigenetic features, which include histone posttranslational modifications (PTMs) and histone variants, can result in the inappropriate expression or silencing of genes, often leading to diseased states, including cancer. The investigation of histone PTMs and variants in the context of clinical samples has highlighted their importance as biomarkers for patient stratification and as key players in aberrant epigenetic mechanisms potentially targetable for therapy. Mass spectrometry (MS) has emerged as the most powerful and versatile tool for the comprehensive, unbiased and quantitative analysis of histone proteoforms. In recent years, these approaches-which we refer to as "epi-proteomics"-have demonstrated their usefulness for the investigation of epigenetic mechanisms in pathological conditions, offering a number of advantages compared with the antibody-based methods traditionally used to profile clinical samples. In this review article, we will provide a critical overview of the MS-based approaches that can be employed to study histone PTMs and variants in clinical samples, with a strong focus on the latest advances in this area, such as the analysis of uncommon modifications and the integration of epi-proteomics data into multi-OMICs approaches, as well as the challenges to be addressed to fully exploit the potential of this novel field of research.

Keywords:  Cancer; Epigenetics; Histone posttranslational modification; Histone variant; Histone-modifying enzyme; Mass spectrometry; Proteomics

DOI:  https://doi.org/10.1186/s13148-022-01371-y
Elife. 2022 Nov 18. pii: e80210. [Epub ahead of print]11

Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode.

Lu Hu, Yang Sun, Shun Liu, Hannah Erb, Alka Singh, Junhao Mao, Xuelian Luo, Xu Wu.

  The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers, and is associated with cancer cell proliferation, survival and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1-4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong anti-proliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency.

Keywords:  biochemistry; chemical biology; human

DOI:  https://doi.org/10.7554/eLife.80210
Nat Commun. 2022 Nov 17. 13(1): 7047

mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters.

Yuanhui Liu, Nancy G Azizian, Delaney K Sullivan, Yulin Li.

Chemotherapy can eradicate a majority of cancer cells. However, a small population of tumor cells often survives drug treatments through genetic and/or non-genetic mechanisms, leading to tumor recurrence. Here we report a reversible chemoresistance phenotype regulated by the mTOR pathway. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity in vitro and in vivo and predicts better survival among various human cancers. Persister cells display a senescence phenotype. Inhibition of mTOR does not induce cellular senescence per se, but rather promotes the survival of senescent cells through regulation of autophagy and G2/M cell cycle arrest, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant senescence state.

DOI: https://doi.org/10.1038/s41467-022-34890-6
Front Endocrinol (Lausanne). 2022 ;13 1047433

Identification of risk model based on glycolysis-related genes in the metastasis of osteosarcoma.

Wei Huang, Yingqi Xiao, Hongwei Wang, Guanghui Chen, Kaixiang Li.

  Background: Glycolytic metabolic pathway has been confirmed to play a vital role in the proliferation, survival, and migration of malignant tumors, but the relationship between glycolytic pathway-related genes and osteosarcoma (OS) metastasis and prognosis remain unclear.Methods: We performed Gene set enrichment analysis (GSEA) on the osteosarcoma dataset in the TARGET database to explore differences in glycolysis-related pathway gene sets between primary osteosarcoma (without other organ metastases) and metastatic osteosarcoma patient samples, as well as glycolytic pathway gene set gene difference analysis. Then, we extracted OS data from the TCGA database and used Cox proportional risk regression to identify prognosis-associated glycolytic genes to establish a risk model. Further, the validity of the risk model was confirmed using the GEO database dataset. Finally, we further screened OS metastasis-related genes based on machine learning. We selected the genes with the highest clinical metastasis-related importance as representative genes for in vitro experimental validation.
Results: Using the TARGET osteosarcoma dataset, we identified 5 glycolysis-related pathway gene sets that were significantly different in metastatic and non-metastatic osteosarcoma patient samples and identified 29 prognostically relevant genes. Next, we used multivariate Cox regression to determine the inclusion of 13 genes (ADH5, DCN, G6PD, etc.) to construct a prognostic risk score model to predict 1- (AUC=0.959), 3- (AUC=0.899), and 5-year (AUC=0.895) survival under the curve. Ultimately, the KM curves pooled into the datasets GSE21257 and GSE39055 also confirmed the validity of the prognostic risk model, with a statistically significant difference in overall survival between the low- and high-risk groups (P<0.05). In addition, machine learning identified INSR as the gene with the highest importance for OS metastasis, and the transwell assay verified that INSR significantly promoted OS cell metastasis.
Conclusions: A risk model based on seven glycolytic genes (INSR, FAM162A, GLCE, ADH5, G6PD, SDC3, HS2ST1) can effectively evaluate the prognosis of osteosarcoma, and in vitro experiments also confirmed the important role of INSR in promoting OS migration.

Keywords:  INSR; Osteosarcoma; glycolysis; machine learning; prognostic risk model

DOI:  https://doi.org/10.3389/fendo.2022.1047433
Commun Biol. 2022 Nov 17. 5(1): 1258

A lineage tree-based hidden Markov model quantifies cellular heterogeneity and plasticity.

Farnaz Mohammadi, Shakthi Visagan, Sean M Gross, Luka Karginov, J C Lagarde, Laura M Heiser, Aaron S Meyer.

Individual cells can assume a variety of molecular and phenotypic states and recent studies indicate that cells can rapidly adapt in response to therapeutic stress. Such phenotypic plasticity may confer resistance, but also presents opportunities to identify molecular programs that could be targeted for therapeutic benefit. Approaches to quantify tumor-drug responses typically focus on snapshot, population-level measurements. While informative, these methods lack lineage and temporal information, which are particularly critical for understanding dynamic processes such as cell state switching. As new technologies have become available to measure lineage relationships, modeling approaches will be needed to identify the forms of cell-to-cell heterogeneity present in these data. Here we apply a lineage tree-based adaptation of a hidden Markov model that employs single cell lineages as input to learn the characteristic patterns of phenotypic heterogeneity and state transitions. In benchmarking studies, we demonstrated that the model successfully classifies cells within experimentally-tractable dataset sizes. As an application, we analyzed experimental measurements in cancer and non-cancer cell populations under various treatments. We find evidence of multiple phenotypically distinct states, with considerable heterogeneity and unique drug responses. In total, this framework allows for the flexible modeling of single cell heterogeneity across lineages to quantify, understand, and control cell state switching.

DOI: https://doi.org/10.1038/s42003-022-04208-9
Mutat Res Rev Mutat Res. 2022 Nov 09. pii: S1383-5742(22)00035-7. [Epub ahead of print] 108445

Clonal evolution and expansion associated with therapy resistance and relapse of Colorectal Cancer.

S Anupriya, Averi Chakraborty, Srinivas Patnaik.

  Colorectal cancer (CRC) arises by a continuous process of genetic diversification and clonal evolution. Multiple genes and pathways have a role in tumor initiation and progression. The gradual accumulation of genetic and epigenetic processes leads to the establishment of adenoma and cancer. The important 'driver' mutations in tumor suppressor genes (such as TP53, APC, and SMAD4) and oncogenes (such as KRAS, NRAS, MET, and PIK3CA) confer selective growth advantages and cause CRC advancement. Clonal evolution induced by therapeutic pressure, as well as intra-tumoral heterogeneity, has been a great challenge in the treatment of metastatic CRC. Tumors often develop resistance to treatments as a result of intra-tumor heterogeneity, clonal evolution, and selection. Hence, the development of a multidrug personalized approach should be prioritized to pave the way for therapeutics repurposing and combination therapy to arrest tumor progression. This review summarizes how selective drug pressure can impact tumor evolution, resulting in the formation of polyclonal resistance mechanisms, ultimately promoting cancer progression. Current strategies for targeting clonal evolution are described. By understanding sources and consequences of tumor heterogeneity, customized and effective treatment plans to combat drug resistance may be devised.

Keywords:  Clonal evolution; Colorectal cancer (CRC); Metastasis; Subclonal mutations; Tumor heterogeneity

DOI:  https://doi.org/10.1016/j.mrrev.2022.108445