CHD1, a multifaceted epigenetic remodeler in prostate cancer

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Abstract

Chromatin remodeling proteins contribute to DNA replication, transcription, repair, and recombination. The chromodomain helicase DNA-binding (CHD) family of remodelers plays crucial roles in embryonic development, hematopoiesis, and neurogenesis. As the founding member, CHD1 is capable of assembling nucleosomes, remodeling chromatin structure, and regulating gene transcription. Dysregulation of CHD1 at genetic, epigenetic, and post-translational levels is common in malignancies and other human diseases. Through interacting with different genetic alterations, CHD1 possesses the capabilities to exert oncogenic or tumor-suppressive functions in context-dependent manners. In this Review, we summarize the biochemical properties and dysregulation of CHD1 in cancer cells, and then discuss CHD1’s roles in different contexts of prostate cancer, with an emphasis on its crosstalk with diverse signaling pathways. Furthermore, we highlight the potential therapeutic strategies for cancers with dysregulated CHD1. At last, we discuss current research gaps in understanding CHD1’s biological functions and molecular basis during disease progression, as well as the modeling systems for biology study and therapeutic development.

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Oncogenic Signaling Pathways in The Cancer Genome Atlas

Yuexin Liu, Ilya Shmulevich, Kalle Leinonen … (2018)

Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, P53 and β-catenin/WNT. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

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Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

Katherine A. Hoadley, Christina Yau, Toshinori Hinoue … (2018)

SUMMARY We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

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PARP inhibitors: Synthetic lethality in the clinic.

Christopher J. Lord, Alan Ashworth (2017)

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

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Author and article information

Contributors

Haoyan Li: URI : https://loop.frontiersin.org/people/2110382

Loraine Gigi: URI : https://loop.frontiersin.org/people/2169993

Di Zhao: URI : https://loop.frontiersin.org/people/1240439

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (iso-abbrev): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2234-943X

Publication date (Electronic): 26 January 2023

Publication date Collection: 2023

Volume: 13

Electronic Location Identifier: 1123362

Affiliations

[1] ¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, United States

[2] ² Texas A&M School of Public Health, Texas A&M University, College Station , TX, United States

Author notes

Edited by: Shuai Gao, New York Medical College, United States

Reviewed by: Changmeng Cai, University of Massachusetts Boston, United States; Daisuke Obinata, Nihon University, Japan

*Correspondence: Di Zhao, dzhao2@ 123456mdanderson.org

This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology

Article

DOI: 10.3389/fonc.2023.1123362

PMC ID: 9909554

PubMed ID: 36776288

SO-VID: 7c2a5a83-e054-47b5-8de2-ba6519c1c10d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 13 December 2022

Date accepted : 11 January 2023

Page count

Figures: 3, Tables: 1, Equations: 0, References: 148, Pages: 14, Words: 8339

Funding

Funded by: Cancer Prevention and Research Institute of Texas , doi 10.13039/100004917;

Funded by: National Institutes of Health , doi 10.13039/100000002;

Funded by: Prostate Cancer Foundation , doi 10.13039/100000892;

Funded by: Cancer Prevention and Research Institute of Texas , doi 10.13039/100004917;

Funded by: National Institutes of Health , doi 10.13039/100000002;

This work was supported, for LG, in part by NIH 1R25CA240137-01A1 UPWARDS Training Program (Underrepresented Minorities Working Towards Research Diversity in Science) and CPRIT training Award RP210028 (to LG). This work was supported, for DZ, in part by CPRIT Recruitment of First-Time Tenure-Track Faculty Award RR190021 (to DZ, a CPRIT Scholar in Cancer Research), NIH/NCI R01 CA275990 (to DZ), and Prostate Cancer Foundation Challenge Award FP00016492 (to DZ).

CHD1, a multifaceted epigenetic remodeler in prostate cancer

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Karger: Oncology

Most cited references 148

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

PARP inhibitors: Synthetic lethality in the clinic.

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