SIRT2 promotes cell proliferation and migration through mediating ERK1/2 activation and lactosylceramide accumulation in prostate cancer

Background: Prostate Cancer (PCa) is an age-related malignancy with a high incidence and mortality rate due to lack of efficacy drugs for its therapy in late castration-resistant stage. Sirtuin 2 (SIRT2), a NAD⁺ -dependent protein deacetylase, is associated with age-related diseases. However, SIRT2 roles in PCa are unclear yet.

Methods: Data of SIRT2 expression were extracted from TCGA cohort and GSE54460 cohort. Realtime quantitative PCR and immunohistochemistry were employed to analyze the expression of SIRT2 in PCa tissues. Cell counting Kit-8 assay, lentiviral transduction, flow cytometry, transwell experiments, western blot and metabolomic analysis were performed to explore the functions of SIRT2.

Results: SIRT2 exhibited increased expression in castration-resistant prostate Cancer (CRPC) and neuroendocrine prostate Cancer (NEPC). Overexpression of SIRT2 promoted cell proliferation, the proportion of S phase, migration and invasion, and reduced Apoptosis rate. The increased phosphorylated ERK1/2 indicated the regulation of SIRT2 to cell proliferation, migration and invasion through activation of ERK1/2 pathway. Furthermore, SIRT2 affected cell metabolic profile and induces lactosylceramide production through upregulation of B4GALT5, which further contributes cell migration and invasion.

Conclusions: Our data suggested that SIRT2 is overexpressed in CRPC and NEPC and could promote cell growth and migration through activating ERK1/2 pathway and inducing lactosylceramide production, indicating that SIRT2 has the potential to be a new target for the treatment of PCa.