Abstract B022: Decipher actionable tumor suppressor defects for personalized cancer medicine

Abstract Chromatin remodeling proteins contribute to DNA replication, transcription, repair, and recombination. The chromodomain helicase DNA-binding (CHD) family of remodelers plays crucial roles in embryonic development, neurogenesis, and carcinogenesis. As the founding member, CHD1 is capable of assembling nucleosomes, remodeling chromatin structure, and regulating gene transcription. Dysregulation of CHD1 at genetic, epigenetic, and post-translational levels is common in prostate cancer and other malignancies. Through interacting with different genetic alterations, CHD1 possesses the capabilities to exert oncogenic or tumor-suppressive functions in context-dependent manners. In the past decade, my study uncovered the novel cell-intrinsic and -extrinsic roles of CHD1 during prostate cancer development, progression, and therapy resistance (Nature 2017, Cancer Discover 2020, Cancer Research 2022, Nature Cancer 2024). Cancer genome studies have uncovered a unique subtype of prostate cancer characterized by speckle-type BTB/POZ protein (SPOP) mutations, which stabilize AR and its co-activators and have been associated with prolonged responses to androgen deprivation therapies and favorable prognoses. Loss of CHD1 frequently co-occurs with SPOP mutations; however, how concurrent CHD1 loss impacts SPOP-mutated prostate cancer remains unclear. Most recently, by generating the first-in-the-field genetically engineered mouse models, we provided genetic evidence supporting that CHD1 loss accelerates SPOP-mutated prostate cancer progression and confers resistance to castration in this context. We uncover a non-canonical epigenetic function of CHD1 and demonstrate that CHD1 reprograms lipid metabolism by governing SREBPs. CHD1 loss–induced lipid reprogramming supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors upon castration. Furthermore, the mechanistic studies facilitate the development of a novel biomarker-driven combinatorial therapy for castration-resistant prostate cancer harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging prostate cancer subtype and mechanism of action and provide novel therapeutic strategies for men with advanced prostate cancer. *This research article has been accepted by Nature Cancer for publication. Citation Format: Feiyu Chen, Di Zhao. Decipher actionable tumor suppressor defects for personalized cancer medicine [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B022.