journal contribution
posted on 2025-02-17, 08:20 authored by Juan Jin, Jun Luo, Xiaodong Jin, Kiat Shenq Lim, Yang He, Jiawei Ding, Yan Shen, Yuchen Hou, Hanqing Liu, Xiaoyu Zhu, Jing Zhao, Wenjie Zhou, Hai Huang, Yi Gao, Jun Xiao, Hongchao He, Qunyi Li, Lianxin Liu, Li Chen, Qiang He, Chuanjie Zhang Supplementary Figure 6. In vitro and in vivo assessment of AU-15330 efficacy against FH-deficient RCC in multiple preclinical models, related to Figure 7. A. Dose-response curves and IC50 of FH-intact or FH-deficient cells treated with AU-15330. B. Dose-response curves of UOK-262 cells treated with AU-15330, AU-15139, or AU-16235. C-D. Mouse weight changes measurements (C) (n = 5) and complete blood counts (D) performed on vehicle control and AU-15330 treated mice as in Fig. 7A. E. Representative HE graphs showing the morphology of critical organs in mice treated with an increased amount of AU-15330. F. Representative graphs showing AU-15330 efficacy against FH-mutated RCC organoids with CHD6 depletion. Scale bar: 200 μm. G. Changes in tumour volumes of the subcutaneous PDX models receiving daily i.v. with vehicle or AU-15330 for 8 weeks (n = 8 mice per group). H. BIL signals (left) and quantification (right) of lung metastatic nodes in mice derived from indicated groups. P values were calculated using the two-tailed Student’s t-test (D), 2-way ANOVA followed by Tukey’s multiple comparisons test (F, H). *p < 0.05, **p < 0.01, and ***p < 0.001. ns, no significance.
Funding
National Natural Science Foundation of China (NSFC)
Natural Science Foundation of Shanghai Municipality (上海市自然科学基金)
History
ARTICLE 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.
