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The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response

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Review Article

The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response

  • Jing Zhang 1
  • David J.H. Shih 1
  • Shiaw-Yih Lin* 1
  • 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

*Corresponding Author: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Citation: Jing Zhang, David J.H. Shih and Shiaw-Yih Lin. The Tale of CHD4 in DNA Damage Response and Chemotherapeutic Response, J. Cancer Research and Celllular Therapeutics . Doi: 10.31579/2640-1053/052

Copyright: © 2019 Shiaw-Yih Lin, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.

Received: 20 June 2019 | Accepted: 07 July 2019 | Published: 08 July 2019

Keywords: CHD4; DNA damage response; mutations; chemotherapeutic response

Abstract

The chromatin remodeling factor chromodomain helicase DNA-binding protein 4 (CHD4) is a core component of the nucleosome remodeling and deacetylase (NuRD) complex. Due to its important role in DNA damage repair, CHD4 has been identified as a key determinant in cancer progression, stem cell differentiation, and T cell and B cell development. Accumulating evidence has revealed that CHD4 can function in NuRD dependent and independent manner in response to DNA damage. Mutations of CHD4 have been shown to diminish its functions, which indicates that interpretation of its mutations may provide tangible benefit for patients. The expression of CHD4 play a dual role in sensitizing cancer cells to chemotherapeutic agents, which provides new insights into the contribution of CHD4 to tumor biology and new therapeutic avenues.

Introduction

Known as Mi2β, Chromodomain helicase DNA-binding 4 (CHD4), a highly conserved protein (~250 kDa) in animals and plants [1], is one of members of the SNF2/RAD54 helicase family, which use the energy derived from ATP hydrolysis to remodel nucleosome structure [2, 3]. It comprises a core ATPase/helicase domain flanked by two Plant Homeodomain motifs (PHD fingers) that recognize modifications of histone tails, tandem chromodomains, and carboxyl-terminal domains necessary for transcriptional repression.

The ATPase domain enables CHD4 to use energy from ATP hydrolysis to remodel nucleosomes along DNA [4]. In this context, CHD4 serves as a key component of the nucleosome remodeling and deacetylase (NuRD) complex, which plays an important role in regulation of chromatin structure, gene expression, and cell cycle progression during normal development and tumorigenesis [5, 6]. In addition to CHD4, NuRD also contains a core of two lysine deacetylase proteins, HDAC1 and HDAC2, two chaperone proteins, RBBP4 and RBBP7, together with associated proteins [1, 7, 8]. It is important to point out that CHD4-NuRD complex is recruited to sites by interaction with sequence-specific DNA binding proteins, instead of recognizing specific DNA sequences [9-11]. After the interaction with DNA binding protein, the local chromatin structures are modified through nucleosomes remodeling, histone deacetylation, and promoter decommissioning [12-14]. Therefore, CHD4-NuRD complex has been identified as an integral driver of transcription.

Although CHD4 is defined as core NuRD component, increasing evidence is accumulating that CHD4 also play important NuRD-independent role in the DNA-damage response, cell cycle progression, signal transduction, and overall genome maintenance [8, 15, 16]. An early study shows that CHD4 associates with the CD4 enhancer independently of NuRD to activate CD4 expression during T-cell development[15]. In the Ikaros-deleted thymocyte system, CHD4 functions in a NuRD-independent manner to antagonize PRC2-mediated transcriptional repression [17]. In addition, the PHD fingers of CHD4 enable it to directly bind both un-methylated (H3K4) as well as K9-methylated (H3K9me3) N-terminal tails of histone H3  [18, 19]. The dual properties of CHD4 that both regulate chromatin structure via ATP hydrolysis and bind histone H3 indicate that it involves in different aspects of chromatin accessibility.  

Despite the increasing characterization of this transcriptional regulator, we still know little about the function of CHD4 in cancer progression as a DNA-repair protein. Recent studies suggest the roles CHD4 in both promoting and suppressing tumor growth [20-24]. For instance, CHD4 expression level is positively correlated with the malignant progression of non-small-cell lung cancer [25]. More recently, CHD4 expression was found to be positively correlated with metastatic stage, tumor recurrence and survival status in triple-negative breast cancer (TNBC) [21].  Interestingly, CHD4 is also implicated as a tumor suppressor in some cancer types [22]. We previously reported that CHD4 depletion and CHD4 mutations promote endometrial cancer stemness by activating TGF-beta signaling [23]. In this review, we summarized the role of this transcriptional regulator in DNA repair and its potential roles in the development of novel anti-cancer drugs.

The role of CHD4 in regulating DNA damage response

In response to DNA damage, cells initiate DNA-damage response (DDR) to prevent tumorigenesis [26-28]. The activation of DDR involves in the recruitment of DDR proteins to the damaged sites in an orchestrated manner. Increasing evidence has demonstrated that CHD4 plays an important role in genome integrity by regulating signaling and repair in response to DNA damage [29-31]. However, it is not clear whether CHD4 functions as a part of NuRD or independently of NuRD.

In response to DNA damage, CHD4 can be recruited to the sites of DNA damage by different models. One model is NuRD complex dependent, where CHD4-NuRD complex is rapidly recruited to the sites of DNA damage through the association with Poly(ADP-ribose) polymerase 1 (PARP1) [31-33]. In this model, CHD4 helps set up a transient repressive chromatin structure at sites of DNA damage to facilitate DNA repair. Another model is NuRD complex independent, where CHD4 is recruited to the sites of DNA damage by RING finger ubiquitin ligase 8 (RNF8), which promotes assembly of a subset of DNA repair factors such as RNF168 and BRCA1 at the sites of the DNA damage [16]. In addition, CHD4 can be phosphorylated by the DNA damage response kinases ATM [34, 35] and ATR [36], and in turn CHD4 can also regulate the Tip60-dependent phosphorylation of ATM [37] in response to DNA damage.

However, what is currently unknown is that whether CHD4 functions to maintain genome integrity prior to DNA damage, or it is required to repair damage upon DNA damage. For instance, CHD4 was reported to modulate the expression of RAD51, an essential protein in homologous recombination of DNA, by directly binding to the RAD51 promoter [30]. And loss of CHD4, even without the DNA damage agents, caused DNA damage in glioblastoma cells by decreasing the activity of RAD51 [30]. Interestingly, CHD4 was also shown to be recruited to DNA damage sites in poly(ADP-ribosyl)ation-dependent manner during chromatin remodeling in response to DNA damage induction [31]. Taken together, CHD4 appears to have a key role for DNA repair and cell survival through multiple mechanisms.

CHD4 and its mutations in cancer progression

Cancers with CHD4 mutations showed loss of CHD4 expression. Loss of CHD4 expression was found in over 50% of gastric and colorectal cancers [38]. In endometrial cancer, CHD4 is one of the most frequently mutated tumor suppressor genes and typically sustains missense mutations (instead of deletions) [39, 40]. Despite the highly frequent mutations of CHD4 detected, the functional significance of most CHD4 mutations is unknown. We recently showed that two point mutations of CHD4 (R975H and R1162W) in ATPase domain in endometrial cancer destabilized the CHD4 protein and consequently diminished the function of CHD4, which induces a cancer stem cell phenotype to promote cancer progression [23]. Miki Yamada et al. reported that missense single nucleotide variation p.D140E accelerated the development of cancer [41]. Therefore, interpretation of mutations in CHD4 may provide tangible benefit for patients with cancer in the near term.

In addition to its role in cancer progression, CHD4 play essential roles in stem cell differentiation [14, 42, 43], embryonic development [44, 45], striated muscle identity [46], and T cell [15] and B cell development [47, 48]. Through whole-exome sequencing and web-based gene matching, five individual de novo mutations in CHD4 were identified to cause an intellectual disability syndrome with distinctive dysmorphisms [49]. CHD4 depletion has been shown to sensitize cancer cells to some chemotherapeutic agents [23]. Therefore, these loss-of-function mutations show potential for therapeutic targeting. Together, it is important to identify CHD4 mutations that induce sensitivity to chemotherapeutic agents. A library of all clinically observed CHD4 mutations could be generated by high-throughput cloning in order to identify loss-of-function mutations that confer sensitivity to chemotherapeutic agents.

The role of CHD4 in chemotherapeutic response

CHD4 expression was found to be associated with metastatic stage, tumor recurrence and survival status, and loss of CHD4 expression sensitizes cells to DNA-damaging agents  [37, 50, 51].  We previously demonstrated the importance of CHD4 in controlling HR repair to maintain genome stability, and that deficiency in CHD4 impairs the recruitment of BRIT1 and sensitizes cells to poly (ADP-ribose) polymerase inhibitor treatment [51].  Subsequently, an siRNA screen by Carolian D’Alesio et al. identified CHD4 as a therapeutic target in colon cancer. In this study, CHD4 depletion was found to sensitize colon cancer cells to DNMT inhibitors in reactivating hypermethylated genes [52]. Later, depletion of CHD4 in acute myeloid leukemia blasts was found to sensitize cells both in vitro and in vivo to genotoxic agents daunorubicin and cytarabine [37]. More recently, CHD4 was found to mediate epithelial-mesenchymal transition in TNBC cells, and silencing of CHD4 expression in these cells increase drug sensitivity to cisplatin and PARP1 inhibitor [21].

Interestingly, CHD4 depletion in BRCA2 mutant cells promotes resistance to cisplatin by a mechanism independent of HR but dependent on RAD18 [53]. Loss of CHD4 in BRCA2 mutant PEO1 cells showed enhanced survival against the DNA-damaging agents such as the PARP inhibitor Olaparib, the double-strand break-inducing agent Zeocin, and the DNA polymerase inhibitor aphidicolin [53]. These seemingly contradictory results reveal the intricate mechanisms of CHD4 involved. To date, no therapeutic agents have been reported to exhibit selectivity towards the expression of CHD4. Therefore, CHD4 may be serve as a potential target for the development of new anti-cancer agents.

Conclusion and future directions

Recent progress in understanding the role of CHD4 in response to DNA damage, as discussed above, suggests the importance of designing effective cancer therapeutic agents that target CHD4. However, due to the crucial roles of CHD4 in both promoting and suppressing tumor growth, more knowledge of the fundamental biology downstream of CHD4 should be investigated. Identifying the binding partners of CHD4 and the signaling cascade its involved in will facilitate the generation of models revealing the biological functions of the CHD4 to cancer.

Loss-of-function mutations of CHD4 has been observed in some cancer types. Clinical genome-sequencing projects should be conducted to provide insight into the prevalence of CHD4 mutations in different cancer types and reveal patterns of these mutations. High-throughput screens of compounds associated with CHD4 and its mutations may provide new insights into the contribution of CHD4 aberrations to tumorigenesis and provide new therapeutic avenues.

In addition, the expression of CHD4 plays a dual role in sensitizing cancer cells to chemotherapeutic agents. This dual role mechanism is related to the role of CHD4 in DNA damage repair. However, it is not clear whether or not CHD4 drives resistance and how it does this. As CHD4 frequently associates with DDR proteins to regulate transcription, drugs regulating the activity or the interactions of these proteins may be a more selective approach to inhibiting undesirable CHD4 functions in cancer cells. Also post-translational modification of CHD4 can modulate its function, which offers potentially additional drug targets for novel cancer therapies.

Acknowledgements

This work was supported by a grant from the NCI (R01CA172490) to SYL.

Conflict of Interest
The author Declairs there is no Conflict of Interest.

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Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner