bims-ectoca 2023-04-02 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023‒04‒02
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

The epigenome and the many facets of cancer drug tolerance.
Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma.
Targeting epigenetic regulation for cancer therapy using small molecule inhibitors.
Epigenetic adaptations in drug-tolerant tumor cells.
Epigenetic regulation of autophagy by histone-modifying enzymes under nutrient stress.
Drug-Tolerant Persister Cells After EGFR Tyrosine Kinase Inhibitor Treatment: Their Origin and the Influences From the Tumor Microenvironment.
DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.

Adv Cancer Res. 2023 ;pii: S0065-230X(22)00092-6. [Epub ahead of print]158 1-39

The epigenome and the many facets of cancer drug tolerance.

Paul C Moore, Kurt W Henderson, Marie Classon.

  The use of chemotherapeutic agents and the development of new cancer therapies over the past few decades has consequently led to the emergence of myriad therapeutic resistance mechanisms. Once thought to be explicitly driven by genetics, the coupling of reversible sensitivity and absence of pre-existing mutations in some tumors opened the way for discovery of drug-tolerant persisters (DTPs): slow-cycling subpopulations of tumor cells that exhibit reversible sensitivity to therapy. These cells confer multi-drug tolerance, to targeted and chemotherapies alike, until the residual disease can establish a stable, drug-resistant state. The DTP state can exploit a multitude of distinct, yet interlaced, mechanisms to survive otherwise lethal drug exposures. Here, we categorize these multi-faceted defense mechanisms into unique Hallmarks of Cancer Drug Tolerance. At the highest level, these are comprised of heterogeneity, signaling plasticity, differentiation, proliferation/metabolism, stress management, genomic integrity, crosstalk with the tumor microenvironment, immune escape, and epigenetic regulatory mechanisms. Of these, epigenetics was both one of the first proposed means of non-genetic resistance and one of the first discovered. As we describe in this review, epigenetic regulatory factors are involved in most facets of DTP biology, positioning this hallmark as an overarching mediator of drug tolerance and a potential avenue to novel therapies.

Keywords:  Cancer stem cells; Drug-tolerant persisters; Epigenetics; Histone methylation; Plasticity; Subpopulations; Tumor heterogeneity; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.acr.2022.12.002
Nat Chem Biol. 2023 Mar 27.

Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma.

Hui Si Kwok, Allyson M Freedy, Allison P Siegenfeld, Julia W Morriss, Amanda L Waterbury, Stephen M Kissler, Brian B Liau.

Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and cancer codependencies. Here we discover mutations that confer drug addiction to inhibitors of the transcriptional repressor polycomb repressive complex 2 (PRC2) in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Discontinuation of inhibitor treatment leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Exploiting this vulnerability, we show that inhibition of SETD2 similarly induces the spread of H3K27me3 and blocks lymphoma growth. Collectively, our findings demonstrate that constraints on chromatin landscapes can yield biphasic dependencies in epigenetic signaling in cancer cells. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

DOI: https://doi.org/10.1038/s41589-023-01299-1
Adv Cancer Res. 2023 ;pii: S0065-230X(23)00001-5. [Epub ahead of print]158 73-161

Targeting epigenetic regulation for cancer therapy using small molecule inhibitors.

Amit Kumar, Luni Emdad, Paul B Fisher, Swadesh K Das.

  Cancer cells display pervasive changes in DNA methylation, disrupted patterns of histone posttranslational modification, chromatin composition or organization and regulatory element activities that alter normal programs of gene expression. It is becoming increasingly clear that disturbances in the epigenome are hallmarks of cancer, which are targetable and represent attractive starting points for drug creation. Remarkable progress has been made in the past decades in discovering and developing epigenetic-based small molecule inhibitors. Recently, epigenetic-targeted agents in hematologic malignancies and solid tumors have been identified and these agents are either in current clinical trials or approved for treatment. However, epigenetic drug applications face many challenges, including low selectivity, poor bioavailability, instability and acquired drug resistance. New multidisciplinary approaches are being designed to overcome these limitations, e.g., applications of machine learning, drug repurposing, high throughput virtual screening technologies, to identify selective compounds with improved stability and better bioavailability. We provide an overview of the key proteins that mediate epigenetic regulation that encompass histone and DNA modifications and discuss effector proteins that affect the organization of chromatin structure and function as well as presently available inhibitors as potential drugs. Current anticancer small-molecule inhibitors targeting epigenetic modified enzymes that have been approved by therapeutic regulatory authorities across the world are highlighted. Many of these are in different stages of clinical evaluation. We also assess emerging strategies for combinatorial approaches of epigenetic drugs with immunotherapy, standard chemotherapy or other classes of agents and advances in the design of novel epigenetic therapies.

Keywords:  Bromodomains; DNA methyl transferase; DNA methylation; Epigenetic regulation; Histone acetyltransferases; Histone deacetylase; Histone methyltransferase; Histone-demethylating; Small molecule inhibitors

DOI:  https://doi.org/10.1016/bs.acr.2023.01.001
Adv Cancer Res. 2023 ;pii: S0065-230X(22)00096-3. [Epub ahead of print]158 293-335

Epigenetic adaptations in drug-tolerant tumor cells.

Nilanjana Mani, Ankita Daiya, Rajdeep Chowdhury, Sudeshna Mukherjee, Shibasish Chowdhury.

  Traditional chemotherapy against cancer is often severely hampered by acquired resistance to the drug. Epigenetic alterations and other mechanisms like drug efflux, drug metabolism, and engagement of survival pathways are crucial in evading drug pressure. Herein, growing evidence suggests that a subpopulation of tumor cells can often tolerate drug onslaught by entering a "persister" state with minimal proliferation. The molecular features of these persister cells are gradually unraveling. Notably, the "persisters" act as a cache of cells that can eventually re-populate the tumor post-withdrawal drug pressure and contribute to acquiring stable drug-resistant features. This underlines the clinical significance of the tolerant cells. Accumulating evidence highlights the importance of modulation of the epigenome as a critical adaptive strategy for evading drug pressure. Chromatin remodeling, altered DNA methylation, and de-regulation of non-coding RNA expression and function contribute significantly to this persister state. No wonder targeting adaptive epigenetic modifications is increasingly recognized as an appropriate therapeutic strategy to sensitize them and restore drug sensitivity. Furthermore, manipulating the tumor microenvironment and "drug holiday" is also explored to maneuver the epigenome. However, heterogeneity in adaptive strategies and lack of targeted therapies have significantly hindered the translation of epigenetic therapy to the clinics. In this review, we comprehensively analyze the epigenetic alterations adapted by the drug-tolerant cells, the therapeutic strategies employed to date, and their limitations and future prospects.

Keywords:  Chromatin structure; Drug-tolerant; Epigenetic; Gene expression; Tumor cell; ncRNAs

DOI:  https://doi.org/10.1016/bs.acr.2022.12.006
Cell Death Differ. 2023 Mar 30.

Epigenetic regulation of autophagy by histone-modifying enzymes under nutrient stress.

Young Suk Yu, Hyunkyung Kim, Keun Il Kim, Sung Hee Baek.

Autophagy is an evolutionarily conserved catabolic process that is induced in response to various stress factors in order to protect cells and maintain cellular homeostasis by degrading redundant components and dysfunctional organelles. Dysregulation of autophagy has been implicated in several conditions such as cancer, neurodegenerative diseases, and metabolic disorders. Although autophagy has been commonly considered as a cytoplasmic process, accumulating evidence has revealed that epigenetic regulation within the nucleus is also important for regulation of autophagy. In particular, when energy homeostasis is disrupted, for instance due to nutrient deprivation, cells increase autophagic activity at the transcriptional level, thereby also increasing the extent of overall autophagic flux. The transcription of genes associated with autophagy is strictly regulated by epigenetic factors through a network of histone-modifying enzymes along with histone modifications. A better understanding of the complex regulatory mechanisms of autophagy could reveal potential new therapeutic targets for autophagy-related diseases. In this review, we discuss the epigenetic regulation of autophagy in response to nutrient stress, focusing on histone-modifying enzymes and histone modifications.

DOI: https://doi.org/10.1038/s41418-023-01154-9
J Thorac Oncol. 2023 Apr;pii: S1556-0864(22)01986-4. [Epub ahead of print]18(4): 399-401

Drug-Tolerant Persister Cells After EGFR Tyrosine Kinase Inhibitor Treatment: Their Origin and the Influences From the Tumor Microenvironment.

Hiromichi Ebi.

DOI: https://doi.org/10.1016/j.jtho.2022.12.010
Adv Sci (Weinh). 2023 Mar 25. e2204438

DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.

Xin Wang, Tangjun Zhou, Xiao Yang, Xiankun Cao, Gu Jin, Pu Zhang, Jiadong Guo, Kewei Rong, Baixing Li, Yibin Hu, Kexin Liu, Peixiang Ma, An Qin, Jie Zhao.

  Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain-containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin-proteasome-mediated degradation of NRF2 via competitive binding to the Kelch-like ECH-associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS.

Keywords:  DDRGK domain-containing protein 1; chemoresistance; doxorubicin; osteosarcoma; redox homeostasis

DOI:  https://doi.org/10.1002/advs.202204438