Targeting SOX4/PCK2 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer

Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that SRY-Box transcription factor 4 (SOX4) is upregulated in NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. Methods: To understand the function of SOX4 in the development and progression of NEPC, we detected malignancy characterization after over-expression or knock-down of SOX4 in prostate cancer cells. Xenograft tumors representing NEPC subtypes were analyzed by pathologists. Protein expression profiles were validated in patient tumor tissue. Diagnoses were complemented by transcriptome sequencing and ATAC sequencing of specific cell lines and public clinical datasets. Results: SOX4 expression was significantly elevated in NEPC. Activating SOX4 in non-NEPC cells induced NE transdifferentiation, while silencing it in NEPC cells impeded NEPC progression. SOX4 promote neuroendocrine characteristics by inducing PCK2-mediated metabolism changing. Conclusions: Elevated SOX4 drives NE transdifferentiation in PCa via PCK2-mediated . Altogether, these findings highlight SOX4 as a novel molecule to drive NEPC progression and suggest that it might be a potential therapeutic target for NEPC. Overall design: To investigate the role of SOX4 in the differentiation of prostate cancer cell lines, we established DU145-shSOX4 cell line and DU145-oeSOX4 cell line to investigate whether SOX4 knockdown could repress the neuroendocrine transdifferentiation of NE-like cells. We then performed gene expression profiling analysing data obtained from RNA-seq of DU145-shCon and DU145-shSOX4 cells. We also performed ATAC seq to explore the chromatin accessibility in DU145-oeSOX4 compared with DU145-Vector cells.