Mechanism and therapeutic targeting of abnormal androgenesis in CHD1-deficient prostate cancer

PROJECT SUMMARY Androgen receptor (AR) signaling is a major driver of prostate cancer (PCa) progression. Persistent activation of AR due to aberrant intratumoral androgen synthesis (ITAS) plays pivotal roles in resistance to therapies with the next-generation AR signaling inhibitors (ARSI) such as abiraterone. In castrated males, besides androgens

produced by de novo synthesis from cholesterol, adrenal steroids dehydroepiandrosterone (DHEA) and DHEA- sulfate (DHEA-S) are the major precursors for ITAS. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), encoded by HSD3B1 gene, is a key 3βHSD enzyme that catalyzes the conversion of the adrenal-derived steroids DHEA

and DHEA-S to testosterone. CHD1 is an epigenetic ‘reader’ that selectively recognizes methylated histone H3 lysine 4 such as H3K4me3, a transcription active chromatin mark. The CHD1 gene is deleted in 9-11% of both primary and advanced PCa, stressing the relevance of loss of function of CHD1 in PCa pathogenesis and

progression. It has been shown that loss of CHD1 promotes AR cistrome redistribution and antiandrogen resistance in PCa cells; however, the underlying mechanism remains elusive. Our preliminary data showed that CHD1 interacts with the SIN3A corepressor protein SIN3A and that loss of CHD1 induces elevation of the total

level of pan histone acetylation, increased expression of steroidogenesis genes and ITAS. We also showed that upregulation of steroids genes including HSD3B1 induced by CHD1 loss associated with increased expression of transcription factor HOXC13. Furthermore, we demonstrated that abiraterone treatment partially inhibits

growth of CHD1-deficient cells and this effect is abolished by concomitant depletion of HSD3B1. Based on our novel preliminary data, we hypothesize that CHD1 functions as a transcription repressor by interacting with the SIN3A corepressor, mediating transcription repression of the HOXC13 transcription factor and downregulation

androgenesis genes. However, loss of CHD1 results in transcriptional de-repression of HOXC13, which in turn induces aberrant expression of androgenesis genes, abnormal intratumoral androgen synthesis, and resistance to ARSI therapies in PCa. Aberrantly elevated 3βHSD1 and increased androgenesis represent actionable

vulnerabilities for effective treatment of CHD1-deficient PCa cells. To test these hypotheses, we will determine the molecular mechanism and extent to which CHD1 interacts with SIN3A and modulates histone acetylation and transcriptional outputs in PCa (Aim 1); determine the molecular mechanism and functional importance of

HOXC13 in upregulation of steroidogenesis genes and castration-resistant growth of CHD1-deficient PCa (Aim 2); and determine clinical significance and ant-cancer efficacy of pre-clinical therapeutic targeting of the deregulated CHD1-HOXC13-3βHSD1 signaling axis in PCa (Aim 3). Findings from this application will shed new

light on the novel transcription repression function of CHD1, the pivotal role of the HOXC13-HSD3B1 axis in aberrant androgen synthesis and castration resistance in CHD1-deficient prostate cancer, and identification of new actionable targets for effective treatment of this subtype of prostate cancer.