Abstract 3751: Altered prostatic HOX code is associated with decreased YAP1 expression during neuroendocrine prostate cancer development

Abstract

Abstract Background: Neuroendocrine (NE) phenotype contributes to 25 to 30% androgen deprivation resistant prostate cancer cases. Until now, this aggressive phenotype is untreatable. Therefore, it is urgent to study the molecular mechanism of NE development to reveal therapeutic strategies. Methods: Data were downloaded from CCLE, cBioPortal, and GEO and analyzed by R. RT-qPCR, western-blot, Immunohistochemistry, and Immunofluorescence were used to assess gene expression. Results: Neuroendocrine prostate cancer (NEPCa) develops from prostate adenocarcinoma (AdPCa). We screened and identified the consensus differentially expressed genes across all public NEPCa transcriptome datasets. We found several HOX genes are included. HOXB13 is deceased but HOXB3, HOXD8 are increased in NEPCa. Based on the HOX code (total 39 HOX genes expression) theory, different cell lineages have distinct HOX codes and HOX codes can represent tissue identities, we established 42 HOX codes for 42 cells lineages including prostate through bioinformatics analysis of 1019 cancer cell lines transcriptome. We found NEPCa samples have changed prostatic HOX code. We also found YAP1, a previously characterized oncogene, is decreased in mRNA level in NEPCa than AdPCa. We confirmed the YAP1 protein is not detected in NEPCa human/mouse samples, PDX samples, and cell line samples (NCI-H660). We used YAP1 as a model. We hypothesized that the signaling involved in silencing YAP1 expression can also contribute to NE development. We first confirmed the loss of YAP1 expression in NEPCa cells is under epigenetic control by inducing YAP1 mRNA expression in primary mouse NEPCa cells through epigenetic inhibitors treatments (HDACs/DNA methyltransferase inhibitors). We characterized the YAP1 promoter through data mining chromatin ChIP-seq data and DNA methylation-seq data. We identified and cloned a 3kb DNA fragment across the YAP1 transcription start site as YAP1 regulatory element. We then built a YAP1-promoter-luciferase reporter using this fragment. We also generated a list of transcription factors that can bind the YAP1 regulatory element. We will then confirm the roles of these transcriptional factors in both regulating YAP1 and NE development. We also found YAP1 expression is co-expressed with many HOX genes in human samples. This suggested the potential regulatory function of HOX code to YAP1 expression. Conclusion: We proposed 2 critical events during NE development, changed prostatic HOX code and loss of YAP expression. We identified HOX code change as one of the potential regulatory mechanisms of YAP1. We then proposed to use YAP1 regulatory element as a model system to study the NE development mechanism. Funding: The LSUHS Office of Research SEED awards, NIH R01 CA226285, and Feist-Weiller Cancer Center pre-doc fellowship to SC. Acknowledgment: We acknowledge Feist-Weiller Cancer Center for travel support to SC. Citation Format: Siyuan Cheng, Shu Yang, Yingli Shi, Xiuping Yu. Altered prostatic HOX code is associated with decreased YAP1 expression during neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3751.