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

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.