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

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Fumarate hydratase (FH) deficiency underlies hereditary leiomyomatosis and renal cell carcinoma (RCC), presenting limited therapeutic avenues.
• FH-deficient tumors exhibit unique molecular characteristics that can be exploited for targeted therapies.

Purpose of the Study:

• To identify novel drug targets in FH-deficient RCC using an epigenetic-focused screen.
• To elucidate the molecular mechanisms by which FH loss impacts tumor growth and identify therapeutic vulnerabilities.

Main Methods:

• An epigenetic-focused CRISPR-Cas9 screen with a single-guide RNA library was employed to identify essential regulators in FH-deficient RCC.
• Mechanistic studies investigated the role of chromodomain helicase DNA-binding protein 6 (CHD6) in FH-mutated cells, including its interaction with KEAP1 and NF-κB pathway components.
• In vivo studies evaluated the efficacy of a PROTAC degrader targeting SMARCA2/4 (AU-15330) in FH-mutated RCC models.

Main Results:

• The screen identified CHD6 as a critical regulator of FH-mutated RCC growth.
• FH loss leads to fumarate-induced KEAP1 inactivation, stabilizing CHD6, which then promotes NF-κB-mediated transcription via proinflammatory enhancers.
• CHD6 recruits mSWI/SNF ATPases to maintain enhancer chromatin accessibility.
• The PROTAC degrader AU-15330 effectively suppressed FH-mutated RCC growth in vivo by disrupting CHD6-bound regulatory elements.

Conclusions:

• CHD6 acts as a molecular link between FH deficiency and the assembly of proinflammatory enhancers in RCC.
• Targeting CHD6 and its associated epigenetic vulnerabilities presents a promising therapeutic strategy for FH-deficient renal cell carcinoma.