Abstract PR022: Polycomb dysregulation shapes chromatin bivalency critical for prostate cancer lineage plasticity

Abstract Prostate cancer lineage plasticity, characterized by histologic transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC), is an emerging mechanism of treatment resistance. NEPC accounts for up to 15% of treatment-resistant prostate cancers and is associated with poor prognosis, highlighting an unmet need for new therapies. NEPC lineage reprogramming is primarily driven by epigenetic dysregulation including differential activity of histone and DNA methyltransferases. EZH2, the catalytic component of the Polycomb repressive complex 2 (Polycomb), is overexpressed in most treatment-resistant prostate cancers and is implicated as a driver of disease progression. In this study, we define the differential, lineage-specific action of Polycomb in both PRAD and NEPC subtypes to better understand its role in modulating differentiation and lineage plasticity, and to identify novel targetable drivers of NEPC. Epigenetic H3K27me3 CUT knockout of PROX1 impeded tumor growth in NEPC models, while overexpression of PROX1 in PRAD promoted tumor growth and spontaneous metastases. Transcriptomic and cistromic analyses across models of CRPC and NEPC pointed to PROX1 regulation of neuroendocrine-lineage transcriptional programs. Immunoprecipitation followed by mass spectrometry identified three novel phosphorylated sites in the DNA-binding domain of PROX1 that are critical for its stability and function. In silico analyses of these phosphorylation sites predicted CHEK1 as a potential upstream kinase which could be exploited for therapeutic targeting of PROX1. Our findings provide insights into the potential role for bivalent promoters in Polycomb-mediated lineage reprogramming, which may facilitate forward differentiation in NEPC upon EZH2 inhibition. Further investigation of de-repressed candidates defines the role of PROX1 as a driver of NEPC and a potential therapeutic target. Citation Format: Varadha Balaji Venkadakrishnan, Nathaniel C. E. Voss, Nicole Traphagen, Richa Singh, James Neiswender, Keira Prenza. Sosa, Kenny Weng, Francisca Vazquez, David S. Rickman, Myles Brown, Himisha Beltran. Polycomb dysregulation shapes chromatin bivalency critical for prostate cancer lineage plasticity abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR022.