CHD1 Loss Hijacks SREBP2-mediated Cholesterol Biosynthesis to Fuel SPOP-deficient Prostate Cancer and Confers Resistance to Castration

Androgen receptor (AR) is an important driver in the disease progression of castration-resistant prostate cancer (CRPC). Speckle-type BTB/POZ protein (SPOP) mutations stabilize AR and frequently co-occur with the loss of chromodomain helicase DNA-binding protein 1 (CHD1). We generated a new genetically engineered mouse model and prostate cancer cells model containing CHD1 deletion and SPOP mutation to study the underlying mechanism. We found CHD1 loss–induced cholesterol production supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors, leading to castration resistance. Overall design: Our rapid immunoprecipitation mass spectrometry (RIME) data showed that CHD1 had a notable interaction with chromatin remodeler sucrose non-fermenting-2 homolog (SNF2H). Then we verified the RIME data by performing co-immunoprecipitation (co-IP) assays, and we found that CHD1 forms a complex with SNF2H and ACF1 proteins in multiple PCa cells. Besides, our ChIP-sequencing data revealed that the CHD1 binds to the SREBF2 gene promoter in PCa cells. To further dissect the impact of CHD1 and SNF2H on SREBF2 transcription, we performed Cleavage Under Targets and Release Using Nuclease Sequencing (CUT&RUN) to uncover whether SNF2H co-localized with CHD1 on the promoter region of the SREBF2 gene in SPOP-mutated LNCaP cells in low androgen conditions.