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 pro-inflammatory 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 pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities.

中文翻译：

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染色质解旋酶 CHD6 建立促炎增强子，是 FH 缺陷型肾细胞癌中的合成致死靶标


富马酸盐水合酶 （FH） 缺乏症会导致遗传性平滑肌瘤病和肾细胞癌 （RCC）。FH 缺陷型肿瘤缺乏有效的治疗选择。在这里，我们利用以表观遗传学为重点的单向导 RNA 文库来阐明 FH 缺陷型肿瘤中的潜在药物靶点。筛选确定染色质域解旋酶 DNA 结合蛋白 6 （CHD6） 是 FH 突变 RCC 生长的重要调节因子。在机械上，FH 缺失诱导富马酸介导的琥珀酰化和 KEAP1 失活，阻断随后的泛素蛋白酶体降解 CHD6。稳定的 CHD6 与 p65 形成复合物，建立促炎增强子，从而调节 NF-κB 介导的转录。此外，CHD6 募集 mSWI/SNF ATP 酶以维持 CHD6 结合增强子的染色质可及性。SMARCA2/4 AU-15330 的 PROTAC 降解剂有效消除了与 CHD6 结合的顺式调节元件的结构，并抑制了 FH 突变但非 FH 完整的 RCC 在体内的生长。总的来说，这些数据表明 CHD6 是 FH 缺陷和促炎增强子组装之间的分子桥梁，赋予 FH 缺陷肿瘤表观遗传脆弱性。