Abstract 4753: LSD1 &8211mediated FOXA2/AP1 transcription program drives lineage plasticity in prostate cancer

Abstract Background: While castration-resistant PCa (CRPC) can be further treated with second-generation androgen deprivation therapies (ADTs), the tumor can quickly generate resistance through multiple mechanisms. One critical mechanism is that tumor cells can progress to AR-indifferent stem cell-like (SCL-PCa or SCLPC) or neuroendocrine-like CRPC (NE-PCa or NEPC) through lineage plasticity. However, the underlying molecular basis remains to be determined, and clinical treatment options for these aggressive CRPC subtypes are currently limited. FOXA1 and FOXA2, which are members of the FOXA (Forkhead Box A) protein family, are pioneer transcription factors. While FOXA1 is well known for its function as a critical pioneer factor of AR and pivotal for maintaining AR signaling, the molecular function of FOXA2 in PCa cells is poorly understood despite that FOXA2 is known to be overexpressed in NEPC. Moreover, since FOXA2, like FOXA1, is currently undruggable in the clinic, there is an urgent need to decipher the molecular basis for the chromatin binding of FOXA2 and identify druggable targets that regulate FOXA2 binding and activity in the aggressive FOXA2-positive CRPC. Methods: In the current study, we first examined the role of FOXA2 in tumorigenesis and metastasis by using various in vitro and in vivo assays including mouse subcutaneous injection and zebrafish embryo injection approaches. We then conducted integrated whole genomic transcriptome and cistrome analyses in SCLPC and NEPC cell line models to characterize the activity of FOXA2 on chromatin and to identify its collaborating transcription factors that may play specific functions in promoting SCLPC or NEPC using a series of biochemical and bioinformatic approaches. Results: We found that FOXA2 silencing decreased the growth and metastasis of SCLPC and NEPC cells. Importantly, we discovered that FOXA2 chromatin binding is tightly associated with binding of JUN family proteins (primarily c-Jun) and FOXA2 silencing dramatically interrupted the global chromatin binding of c-Jun and FOSL1. The transcription targets of FOXA2/AP-1 are highly enriched for neuroendocrine and plasticity associated genes and associated with poor clinical outcomes. Furthermore, we also found that FOXA2 chromatin binding is globally enhanced by an epigenetic factor LSD1, and LSD1 inhibition can repress FOXA2/AP-1 activity in multiple CRPC models. Conclusion: Overall, our data indicate that FOXA2 functions to maintain tumor growth and metastasis in SCLPC and NEPC models. Mechanistically, FOXA2 can act as a pioneer factor of AP-1 (c-Jun/FOSL1) and reprogram AP-1 transcription activity. This FOXA2/AP-1 axis is regulated by LSD1 via demethylating FOXA2 protein and LSD1 inhibition represses FOXA2-dependent CRPC tumor progression. These findings provide novel mechanistic insights into the molecular mechanisms for PCa lineage plasticity and treatment resistance. Citation Format: Zifeng Wang, Mingyu Liu, Songqi Zhang, Muqing Li, Susan Patalano, Jill A. Macoska, Dong Han, Shuai Gao, Hansen He, Changmeng Cai. LSD1 &8211mediated FOXA2/AP1 transcription program drives lineage plasticity in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4753.