Histone demethylase LSD1 promotes castration‐resistant prostate cancer by causing widespread gene expression derangements

Abstract Lysine‐specific demethylase 1 (LSD1), a histone demethylase crucial for embryonic development and tissue differentiation, has an undefined role in prostate cancer (PCa), especially castration‐resistant PCa. The present study represents a pioneering endeavor to comprehensively dissect the function of LSD1 within the PCa landscape. Our investigations revealed that attenuation of LSD1 expression exerts multiple inhibitory effects on PCa cells. Specifically, it curtails the proliferation and colony‐forming ability of PC‐3 cells, concomitantly promotes apoptosis, and impedes cell invasion. Notably, knockdown of LSD1 triggers significant perturbations in the expression profiles of pivotal proteins, such as prostate‐specific antigen (PSA), forkhead box A1 (FOXA1), and NKX3.1, thereby shedding new light on the underlying molecular mechanisms governing PCa progression. Leveraging bioinformatics analysis and transcriptome sequencing, we unearthed that LSD1 knockdown precipitates widespread gene expression dysregulation, with 3166 genes exhibiting differential expression patterns, which in turn impact a broad spectrum of cellular processes. Importantly, we identified that LSD1 modulates the methylation modification of histone H3 lysine 4 monomethylation (H3K4me1) in the promoter region of matrix metallopeptidase 13 (MMP13), thereby orchestrating its expression. In both orthotopic and metastatic tumor models, as well as in vitro cell cultures, the LSD1 inhibitor GSK2879552 demonstrated potent efficacy in suppressing PCa progression. To sum up, this study not only uncovers the oncogenic role of LSD1 in PCa but also validates the therapeutic promise of GSK2879552, furnishing novel perspectives and prospective targets for the clinical management of PCa.