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

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: To deconvolute CHD1's biological function and mechanism of action in SPOP-mutated tumors, we performed single-cell RNA sequencing (scRNA-seq) analysis of PSp and PCSp GEMM. To this end, we performed surgical castration on 9-month-old PSp and PCSp GEM mice (n=2 per cohort), and one month later, we collected the whole prostate tumors for scRNA-seq.