bims-ectoca 2022-03-06 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–03–06
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Discovery of Potent and Isoform-Selective Histone Deacetylase Inhibitors Using Structure-Based Virtual Screening and Biological Evaluation.
Cell-type heterogeneity: Why we should adjust for it in epigenome and biomarker studies.
Emerging roles of JMJD3 in cancer.
Chemical Biology Approaches to Identify and Profile Interactors of Chromatin Modifications.
Cancer epigenetics: promises and pitfalls for cancer therapy.
HyperChIP: identification of hypervariable signals across ChIP-seq or ATAC-seq samples.
CTCF supports preferentially short lamina-associated domains.
MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.
An overview of the development of EED inhibitors to disable the PRC2 function.
Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells.
KDM1A/LSD1 as a promising target in various diseases treatment by regulating autophagy network.
Mechanical determinants of chromatin topology and gene expression.

Mol Inform. 2022 Feb 27.

Discovery of Potent and Isoform-Selective Histone Deacetylase Inhibitors Using Structure-Based Virtual Screening and Biological Evaluation.

Zhe Peng, Quanfeng Zhao, Xiaoyan Tian, Tiantian Lei, Rongfeng Xiang, Lin Chen, Yang Yang.

  Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC-27, AGS, MDA-MB-231, A549, MCF-7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC-27 cells-derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC-targeting inhibitor for solid tumor therapy.

Keywords:  HDACs·pharmacophore modelling·virtual screening·molecular docking·solid tumor therapy

DOI:  https://doi.org/10.1002/minf.202100295
Clin Epigenetics. 2022 02 28. 14(1): 31

Cell-type heterogeneity: Why we should adjust for it in epigenome and biomarker studies.

Luo Qi, Andrew E Teschendorff.

  Most studies aiming to identify epigenetic biomarkers do so from complex tissues that are composed of many different cell-types. By definition, these cell-types vary substantially in terms of their epigenetic profiles. This cell-type specific variation among healthy cells is completely independent of the variation associated with disease, yet it dominates the epigenetic variability landscape. While cell-type composition of tissues can change in disease and this may provide accurate and reproducible biomarkers, not adjusting for the underlying cell-type heterogeneity may seriously limit the sensitivity and precision to detect disease-relevant biomarkers or hamper our understanding of such biomarkers. Given that computational and experimental tools for tackling cell-type heterogeneity are available, we here stress that future epigenetic biomarker studies should aim to provide estimates of underlying cell-type fractions for all samples in the study, and to identify biomarkers before and after adjustment for cell-type heterogeneity, in order to obtain a more complete and unbiased picture of the biomarker-landscape. This is critical, not only to improve reproducibility and for the eventual clinical application of such biomarkers, but importantly, to also improve our molecular understanding of disease itself.

Keywords:  Cell-type deconvolution; Cell-type heterogeneity; Classification; DNA methylation; Epigenetic biomarkers

DOI:  https://doi.org/10.1186/s13148-022-01253-3
Clin Transl Oncol. 2022 Mar 03.

Emerging roles of JMJD3 in cancer.

Maryam Farzaneh, Zeinab Kuchaki, Fatima Rashid Sheykhahmad, Seyed Mohammadmahdi Meybodi, Yusef Abbasi, Effat Gholami, Farhoodeh Ghaedrahmati, Omid Anbiayee.

  Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.

Keywords:  Cancer; Epigenome; Invasion; JMJD3; Metastasis

DOI:  https://doi.org/10.1007/s12094-021-02773-9
ACS Chem Biol. 2022 Mar 03.

Chemical Biology Approaches to Identify and Profile Interactors of Chromatin Modifications.

Garrison A Nickel, Katharine L Diehl.

In eukaryotes, DNA is packaged with histone proteins in a complex known as chromatin. Both the DNA and histone components of chromatin can be chemically modified in a wide variety of ways, resulting in a complex landscape often referred to as the "epigenetic code". These modifications are recognized by effector proteins that remodel chromatin and modulate transcription, translation, and repair of the underlying DNA. In this Review, we examine the development of methods for characterizing proteins that interact with these histone and DNA modifications. "Mark first" approaches utilize chemical, peptide, nucleosome, or oligonucleotide probes to discover interactors of a specific modification. "Reader first" approaches employ arrays of peptides, nucleosomes, or oligonucleotides to profile the binding preferences of interactors. These complementary strategies have greatly enhanced our understanding of how chromatin modifications effect changes in genomic regulation, bringing us ever closer to deciphering this complex language.

DOI: https://doi.org/10.1021/acschembio.1c00794
FEBS J. 2022 03;289(5): 1156-1159

Cancer epigenetics: promises and pitfalls for cancer therapy.

Eleni Skourti, Paraminder Dhillon.

  Over the past few decades, epigenetic regulators have emerged as major players in cellular processes that drive cancer initiation and progression, and subsequently modulate the responsiveness of cancers to therapeutic agents. This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer. The diverse topics explored herein range from the roles of transposable elements and chromatin architecture in cancer and the most recent research advances on cancer-associated histone variants (oncohistones), to the effects of altered epigenetics on transcription and advanced cancer cell phenotypes. Moreover, the prospective key function of cancer metabolism in linking epigenetics and transcriptional regulation, and the potential of epigenetics for targeted cancer therapeutics is discussed. We hope that this collection of articles will give readers an enlightening overview of the most recent advances in the fast-moving field of cancer epigenetics.

Keywords:  DNA methylation; cancer epigenetics; chromatin; histone modifications; transcriptional regulation

DOI:  https://doi.org/10.1111/febs.16395
Genome Biol. 2022 Feb 28. 23(1): 62

HyperChIP: identification of hypervariable signals across ChIP-seq or ATAC-seq samples.

Haojie Chen, Shiqi Tu, Chongze Yuan, Feng Tian, Yijing Zhang, Yihua Sun, Zhen Shao.

  Identifying genomic regions with hypervariable ChIP-seq or ATAC-seq signals across given samples is essential for large-scale epigenetic studies. In particular, the hypervariable regions across tumors from different patients indicate their heterogeneity and can contribute to revealing potential cancer subtypes and the associated epigenetic markers. We present HyperChIP as the first complete statistical tool for the task. HyperChIP uses scaled variances that account for the mean-variance dependence to rank genomic regions, and it increases the statistical power by diminishing the influence of true hypervariable regions on model fitting. A pan-cancer case study illustrates the practical utility of HyperChIP.

Keywords:  ATAC-seq; ChIP-seq; Epigenetic heterogeneity; Hypervariable regions; Large-scale cancer studies

DOI:  https://doi.org/10.1186/s13059-022-02627-9
Chromosome Res. 2022 Mar 03.

CTCF supports preferentially short lamina-associated domains.

Lukasz Stanislaw Kaczmarczyk, Nehora Levi, Tamar Segal, Mali Salmon-Divon, Gabi Gerlitz.

  More than one third of the mammalian genome is in a close association with the nuclear lamina, thus these genomic regions were termed lamina-associated domains (LADs). This association is fundamental for many aspects of chromatin biology including transcription, replication, and DNA damage repair. LADs association with the nuclear envelope is thought to be dependent on two major mechanisms: The first mechanism is the interaction between nuclear membrane proteins such as LBR with heterochromatin modifications that are enriched in LADs chromatin. The second mechanism is based on proteins that bind the borders of the LADs and support the association of the LADs with the nuclear envelope. Two factors were suggested to support the second mechanism: CCCTC-binding factor (CTCF) and YY1 based on their enriched binding to LADs borders. However, this mechanism has not been proven yet at a whole genome level. Here, to test if CTCF supports the LADs landscape, we generated melanoma cells with a partial loss of function (pLoF) of CTCF by the CRISPR-Cas9 system and determined the LADs landscape by lamin B ChIP-seq analysis. We found that under regular growth conditions, CTCF pLoF led to modest changes in the LADs landscape that included an increase in the signal of 2% of the LADs and a decrease in the signal of 8% of the LADs. However, CTCF importance for the LADs landscape was much higher upon induction of a chromatin stress. We induced chromatin stress by inhibiting RNA polymerase II, an intervention that is known to alter chromatin compaction and supercoiling. Notably, only in CTCF pLoF cells, the chromatin stress led to the dissociation of 7% of the LADs from the lamina. The CTCF-dependent LADs had almost three times shorter median length than the non-affected LADs, were enriched in CTCF binding at their borders, and were higher in their facultative-status (cell-type specific). Thus, it appears that CTCF is a key factor in facilitating the association of short facultative LADs with the nuclear lamina upon chromatin stress.

Keywords:  Chromatin; LADs; Nuclear architecture; Nuclear envelope; Transcription

DOI:  https://doi.org/10.1007/s10577-022-09686-5
Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00108-3. [Epub ahead of print]82(5): 1066-1077.e7

MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.

Sotirios D Zervopoulos, Aristeidis E Boukouris, Bruno Saleme, Alois Haromy, Saymon Tejay, Gopinath Sutendra, Evangelos D Michelakis.

  The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points. A decrease in nuclear MFN2 levels decreases mitochondria tethering and nPDC levels. Mitochondrial PDC crosses the NE and interacts with lamin A, forming a ring below the NE before crossing through the lamin layer into the nucleoplasm, in areas away from NPCs. Effective blockage of NPC trafficking does not decrease nPDC levels. The PDC-lamin interaction is maintained during cell division, when lamin depolymerizes and disassembles before reforming daughter nuclear envelopes, providing another pathway for nPDC entry during mitosis. Our work provides a different angle to understanding mitochondria-to-nucleus communication and nuclear metabolism.

Keywords:  acetylation; cell cycle; lamin; metabolism; mitochondria; mitofusin; nucleus; protein trafficking; pyruvate dehydrogenase complex; tethering

DOI:  https://doi.org/10.1016/j.molcel.2022.02.003
RSC Med Chem. 2022 Jan 27. 13(1): 39-53

An overview of the development of EED inhibitors to disable the PRC2 function.

Kai-Lu Liu, Kongkai Zhu, Hua Zhang.

Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represents the main strategy in the development of PRC2 inhibitors. Although significant progress has been made, new problems also emerge, e.g. the drug resistance caused by secondary mutations. In recent years, more and more efforts have shifted to another new strategy - targeting embryonic ectoderm development (EED) to disrupt its major interactions with other components, which are necessary to the PRC2 function, and some promising results have been obtained. This review summarizes the recent development of EED inhibitors as possible chemotherapy for cancer treatment, which could help accelerate future related research work.

DOI: https://doi.org/10.1039/d1md00274k
J Oncol. 2022 ;2022 6737248

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells.

Dong Young Kang, Nipin Sp, Kyoung-Jin Jang, Eun Seong Jo, Se Won Bae, Young Mok Yang.

Embryonic cancer cells (CSCs) could cause different types of cancer, a skill that makes them even more dangerous than other cancer cells. Identifying CSCs using natural products is a good option as it inhibits the recurrence of cancer with moderate various effects. Ursolic acid (UA) is a pentacyclic triterpenoid extracted from fruit and herbal remedies and has known anticancer functions against various cancer cells. However, its potential against CSCs remains uncertain. This study was planned to examine the induction of cell apoptosis by the UA. For cell signaling studies, we performed experiments, which are real-time qPCR and immunoblotting. Also, various cellular processes were analyzed using flow cytometry. The results raised a barrier to cell proliferation by the UA in NTERA-2 and NCCIT cells. Morphological studies also confirmed the UA's ability to cause cell death in embryonic CSCs. Examination of cell death importation showed that the UA formed the expression of the iNOS and thus the cell generation and mitochondrial reactive oxygen generation, which created a reaction to cellular DNA damage by raising the protein levels of phospho-histone ATR and ATM. In addition, the UA created the binding of the G0/G1 cell cycle to NTERA-2 and NCCIT cells, improved the expression levels of p21 and p27, and reduced the expression levels of CDK4, cyclin D1, and cyclin E, confirming the UA's ability to initiate cell cycle arrest. Finally, the UA created an internal mechanism of apoptosis in the embryonic CSC using BAX and cytochrome c regulation as well as the regulation of BCL-xL and BCL-2 proteins. Therefore, UA could be the best candidate for targeting CSCs and thus suppressing the emergence of cancer.

DOI: https://doi.org/10.1155/2022/6737248
Biomed Pharmacother. 2022 Feb 28. pii: S0753-3322(22)00150-0. [Epub ahead of print]148 112762

KDM1A/LSD1 as a promising target in various diseases treatment by regulating autophagy network.

Ting Ma, Anqi Li, Yueyang Guo, Shaotong Li, Meng Li, Siqi Feng, Hongmin Liu.

  Epigenetics refers to alterations in gene expressions that are reversible and stable, but do not involve changes in DNA sequences. In recent years, an increasing number of studies have shown that epigenetics plays a critical role in autophagy, which can be schematized as a biological process comprising of the following steps: autophagy signal activation, autophagic vesicle elongation, autophagosome maturation and autophagosome-lysosome fusion. As previously reported, autophagy can maintain intracellular homeostasis and autophagy dysfunction will lead to various diseases. For instance, the abnormal expression of genes involved in autophagy can result in the occurrence of many cancers and atherosclerosis. It is also well known that epigenetic modifications can affect autophagy related genes expressions and modulate other signaling molecular involved in autophagy. As an important epigenetic enzyme, LSD1 (lysine specific demethylase 1) plays an essential role in modulating autophagy. On one hand, LSD1 directly regulates autophagy-related genes expressions, including ATGs, Beclin-1, LC3 and SQSTM1/p62. On the other hand, inhibition of LSD1 can activate autophagy through regulating the activities of some other proteins such as p53, SESN2, mTORC1 and PTEN. Since autophagy activation is tightly related to the occurrence of various diseases and can be induced by LSD1 inhibition, development of LSD1 inhibitors will provide a new direction to treat such diseases. In this review, we described the mechanisms by which LSD1 regulates autophagy in different manners and how autophagic dysfunction leads to diseases occurrence. In addition, some LSD1 inhibitors used to treat diseases through modulating autophagy are also summarized in our review.

Keywords:  Autophagy; Diseases; Inhibitors; LSD1

DOI:  https://doi.org/10.1016/j.biopha.2022.112762
Nucleus. 2022 Dec;13(1): 94-115

Mechanical determinants of chromatin topology and gene expression.

Rajiv Kumar Jha, David Levens, Fedor Kouzine.

  The compaction of linear DNA into micrometer-sized nuclear boundaries involves the establishment of specific three-dimensional (3D) DNA structures complexed with histone proteins that form chromatin. The resulting structures modulate essential nuclear processes such as transcription, replication, and repair to facilitate or impede their multi-step progression and these contribute to dynamic modification of the 3D-genome organization. It is generally accepted that protein-protein and protein-DNA interactions form the basis of 3D-genome organization. However, the constant generation of mechanical forces, torques, and other stresses produced by various proteins translocating along DNA could be playing a larger role in genome organization than currently appreciated. Clearly, a thorough understanding of the mechanical determinants imposed by DNA transactions on the 3D organization of the genome is required. We provide here an overview of our current knowledge and highlight the importance of DNA and chromatin mechanics in gene expression.

Keywords:  3D genome; DNA supercoiling; Transcription; cell cycle; chromatin; cohesin; epigenetics; loop extrusion; psoralen; topoisomerase

DOI:  https://doi.org/10.1080/19491034.2022.2038868