Chromatin Helicase CHD6 Establishes Proinflammatory Enhancers and Is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma

Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA-binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin-proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish proinflammatory enhancers and thereby regulate NF-κB-mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and proinflammatory enhancer assembly that endows FH-deficient tumors with epigenetic vulnerabilities. Significance: CHD6 links FH deficiency to aberrant NF-κB activity in renal cell carcinoma, highlighting an epigenetic vulnerability for this rare tumor subtype.

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Publication Details

Journal
Cancer Research
Published
2024-11-26
DOI
https://doi.org/10.1158/0008-5472.can-24-0787
Citations
7
Primary Topic
Renal cell carcinoma treatment
Type
article
Field-Weighted Citation Impact
2.93
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article

Chromatin Helicase CHD6 Establishes Proinflammatory Enhancers and Is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma

Jun Xiao, Qunyi Li, Qiang He, Chuanjie Zhang et al.
7 citations
Cancer Research
Renal cell carcinoma treatment
2.93
article

Chromatin Helicase CHD6 Establishes Proinflammatory Enhancers and Is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma

Jun Xiao, Qunyi Li, Qiang He, Chuanjie Zhang, Jing Zhao, Li Chen, Jiawei Ding, Hongchao He, Xiaodong Jin, Jun Luo, Yuchen Hou, Kiat Shenq Lim, Hanqing Liu, Yang He, Yan Shen, Xiaoyu Zhu, Yi Gao, Hai Huang, Wenjie Zhou, Lianxin Liu
article en
7 citations

Abstract

Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA-binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin-proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish proinflammatory enhancers and thereby regulate NF-κB-mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and proinflammatory enhancer assembly that endows FH-deficient tumors with epigenetic vulnerabilities. Significance: CHD6 links FH deficiency to aberrant NF-κB activity in renal cell carcinoma, highlighting an epigenetic vulnerability for this rare tumor subtype.

Cancer ResearchVol. 85(4)
Zhejiang Chinese Medical University (CN), Tongji University (CN), University of Science and Technology of China (CN), The University of Texas MD Anderson Cancer Center (US), Fudan University (CN), Ruijin Hospital (CN), Biotechnology Research Center (IR), Children's Hospital of Zhejiang University (CN), Shanghai Xuhui Central Hospital (CN), Shanghai East Hospital (CN), Shanghai Tenth People's Hospital (CN), Huashan Hospital (CN)
Good health and well-being
Openalex Percentile: Top 8%
Renal cell carcinoma treatment
2.93
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