CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

Oyama, Yoshiko; Shigeta, Shogo; Tokunaga, Hideki; Tsuji, Kiichiro; Ishibashi, Masayoshi; Shibuya, Yasuyuki; Shimada, Muneaki; Yasuda, Jun; Yaegashi, Nobuo

doi:10.1371/journal.pone.0251079

Cited by 17 publications

(8 citation statements)

References 60 publications

(78 reference statements)

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“…Of these 32 genes, many have been identified as having varying roles in ovarian cancer progression and prognosis. Elevated abundances of AHNAK, ANXA1, and LAMA3 have been correlated with suppressed ovarian cancer growth and improved survival. − CHD4, PFKFB3, and RSF1 have been associated with the regulation of drug response. − The expression of FLI-1, KCD5, and PRSS3 has been associated with poor survival, and these proteins are potential prognostic markers. − TP53 is also strongly linked to HGSOC as it is mutated in most HGSOC patients, leading to a gain or loss of function . Other DNA damage repair factors were also identified as significant across the CD1 and CD2 conditions: PRDKC, PARP9, and XRCC6 (Figure D, Table S5).…”

Section: Resultsmentioning

confidence: 99%

Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

Duda,

Thomas

2023

ACS Pharmacol. Transl. Sci.

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High-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy in women. The low survival rate is largely due to drug resistance. Approximately 80% of patients who initially respond to treatment relapse and become drug-resistant. The lack of effective second-line therapeutics remains a substantial challenge for BRCA-1/2 wild-type HGSOC patients. Histone Deacetylases (HDACs) are promising targets in HGSOC treatment; however, the mechanism and efficacy of HDAC inhibitors are understudied in HGSOC. In order to consider HDACs as a treatment target, an improved understanding of their function within HGSOC is required. This includes elucidating HDAC6-specific protein–protein interactions. In this study, we carried out substrate trapping followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate HDAC6 catalytic domain (CD)-specific interactors in the context of BRCA-1/2 wild-type HGSOC. Overall, this study identified new HDAC6 substrates that may be unique to HGSOC. The HDAC6-CD1 mutant condition contained the largest number of significant proteins compared to the CD2 mutant and the CD1/2 mutant conditions, suggesting the HDAC6-CD1 domain has catalytic activity that is independent of CD2. Among the identified substrates were proteins involved in DNA damage repair including PARP proteins. These findings further justify the use of HDAC inhibitors as a combination treatment with platinum chemotherapy agents and PARP inhibitors in HGSOC.

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Section: Resultsmentioning

confidence: 99%

Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

Duda,

Thomas

2023

ACS Pharmacol. Transl. Sci.

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“…Hence, targeting of SMARCA5 has recently shown promise as a chemotherapeutic strategy due to increased genomic instability in cancer. The SMARCA5 inhibitor ED2-AD101 was applied to modulate SMARCA5 activity in ovarian cancer cells [35]. However, this compound lacked speci city and also targeted the chromodomain-helicase-DNA-binding protein 4 (CHD4), resulting in off-target effects.…”

Section: Discussionmentioning

confidence: 99%

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer

xu,

Li,

Xiong

et al. 2024

Preprint

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The chromatin-remodeling enzyme SMARCA5 plays a key role in DNA-templated events including transcription, DNA replication, and DNA repair. Loss of function of the SMARCA5 can cause neurodevelopmental disorder and Williams syndrome. However, the molecular mechanism underlying the regulation of SMARCA5 in prostate cancer remains largely elusive. Here, we report that the deubiquitinating enzyme USP3 directly interacts with SMARCA5 and removes K63-linked polyubiquitination of SMARCA5 to maintain its stability, which promotes DNA damage repair and chemotherapy resistance. Depletion of USP3 or SMARCA5 promoted PCa cells sensitive to docetaxel and overexpression of USP3 restored the cells resistance to docetaxel treatment in SMARCA5 silenced cells in vitro and vivo. Clinically, USP3 was significantly up-regulated in prostate cancer tissues and positively associated with SMARCA5 expression. Collectively, our findings uncover a novel molecular mechanism for the USP3-SMARCA5 axis in regulating DSB repair with an important role in chemotherapy response in human prostate cancers, highlighting that targeting USP3-SMARCA5 axis could be a valuable strategy to treat USP3/SMARCA5-overexpressing chemotherapy-resistant patients and improve drug treatment.

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“…Ultimately, Oyama et al introduced the first-in-class SMARCA5/CHD4 inhibitor ED2-AD101 in ovarian cancer cells. A novel possible treatment approach was shown, as the inhibitor sensitized the cells to DNA damage inducing platinum agents 55 .…”

Section: Discussionmentioning

confidence: 99%

CHD4 acts as a prognostic factor and drives radioresistance in HPV negative HNSCC

Geyer,

Reuning

et al. 2024

Sci Rep

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Despite great efforts in improving existing therapies, the outcome of patients with advanced radioresistant HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. The chromatin remodeler Chromodomain helicase DNA binding protein 4 (CHD4) is involved in different DNA-repair mechanisms, but the role and potential in HNSCC has not been explored yet. In the present study, we evaluated the prognostic significance of CHD4 expression using in silico analysis of the pan-cancer dataset. Furthermore, we established a monoclonal HNSCC CHD4 knockdown cell clone utilizing the CRISPR/Cas9 system. Effects of lower CHD4 expression on radiosensitivity after increasing doses of ionizing radiation were characterized using clonogenic assays and cell numbers. The in silico analysis revealed that high CHD4 expression is associated with significant poorer overall survival of HPV-negative HNSCC patients. Additionally, the knockdown of CHD4 significantly increased the radiosensitivity of HNSCC cells. Therefore, CHD4 might be involved in promoting radioresistance in hard-to-treat HPV-negative HNSCC entities. We conclude that CHD4 could serve as a prognostic factor in HPV-negative HNSCC tumors and is a potential target protein overcoming radioresistance in HNSCC. Our results and the newly established cell clone laid the foundation to further characterize the underlying mechanisms and ultimately use CHD4 in HNSCC therapies.

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CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

Cited by 17 publications

References 60 publications

Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer

CHD4 acts as a prognostic factor and drives radioresistance in HPV negative HNSCC

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