OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer

Abstract

Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.

Profilin 2 isoform expression is associated with lung metastasis of colorectal cancer according to a comprehensive gene expression study using a mouse model

“…Research on the functions of PFN2a has primarily focused on cell migration and the mammalian nervous system, including synaptic vesicle exocytosis and neuronal excitability ( 42 ). The relationship between PFN2 and lung, breast, and prostate cancers was previously investigated ( 17 , 39 , 43 , 44 ). PFN2 regulates growth by inhibiting nuclear localization of histone deacetylase 1 (HDAC1) in lung cancer ( 43 ).…”

Targeting phase separation on enhancers induced by transcription factor complex formations as a new strategy for treating drug-resistant cancers

“…Therefore, dysregulation of collaborating TFs can dramatically change the pattern of AR-binding sites between treatment-naïve PC and CRPC (12,92,93). AR-binding genes unique to CRPC were not AR-regulated in treatment-naïve PC cells (92)(93)(94)(95)(96)(97). Moreover, the ligand-independent splice variant of AR, AR-V7, also facilitates AR activation in PC under castration conditions.…”

Exploring androgen receptor signaling pathway in prostate cancer: A path to new discoveries

“…[3][4][5] Additionally, in organoids derived from patients with neuroendocrine prostate cancer, OCT1 induces distinct target genes involved in the proliferation of neuronal cells. 58 These shifts in TFs and their target genes are important for understanding the biological behavior of CRPC and identifying new therapeutic targets. Particularly noteworthy are the ribosome-targeting drugs CX-5461 and CX-6258 and pyrroleimidazole polyamide.…”

“…Furthermore, specific TFs, including SOX2 , BRN2 , or ONECUT2 , are driver genes for the further progression of CRPC to AR‐negative neuroendocrine prostate cancer 3–5 . Additionally, in organoids derived from patients with neuroendocrine prostate cancer, OCT1 induces distinct target genes involved in the proliferation of neuronal cells 58 . These shifts in TFs and their target genes are important for understanding the biological behavior of CRPC and identifying new therapeutic targets.…”