Succinylation of CTBP1 mediated by KAT2A suppresses its inhibitory activity on the transcription of CDH1 to promote the progression of prostate cancer

Prostate cancer is a complex disease that affects millions of men globally, predominantly in high human development index regions. Patients with localized disease at a low to intermediate risk of recurrence generally have a favourable outcome of 99% overall survival for 10 years if the disease is detected and treated at an early stage. Key genetic alterations include fusions of TMPRSS2 with ETS family genes, amplification of the MYC oncogene, deletion and/or mutation of PTEN and TP53 and, in advanced disease, amplification and/or mutation of the androgen receptor (AR). Prostate cancer is usually diagnosed by prostate biopsy prompted by a blood test to measure prostate-specific antigen levels and/or digital rectal examination. Treatment for localized disease includes active surveillance, radical prostatectomy or ablative radiotherapy as curative approaches. Men whose disease relapses after prostatectomy are treated with salvage radiotherapy and/or androgen deprivation therapy (ADT) for local relapse, or with ADT combined with chemotherapy or novel androgen signalling-targeted agents for systemic relapse. Advanced prostate cancer often progresses despite androgen ablation and is then considered castration-resistant and incurable. Current treatment options include AR-targeted agents, chemotherapy, radionuclides and the poly(ADP-ribose) inhibitor olaparib. Current research aims to improve prostate cancer detection, management and outcomes, including understanding the fundamental biology at all stages of the disease.

Peroxisomes account for ~35% of total H 2 O 2 generation in mammalian tissues. Peroxisomal ACOX 1 (acyl‐CoA oxidase 1) is the first and rate‐limiting enzyme in fatty acid β‐oxidation and a major producer of H 2 O 2 . ACOX 1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 ( SIRT 5) is present in peroxisomes and that ACOX 1 is a physiological substrate of SIRT 5. Mechanistically, SIRT 5‐mediated desuccinylation inhibits ACOX 1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT 5 increases H 2 O 2 production and oxidative DNA damage, which can be alleviated by ACOX 1 knockdown. We show that SIRT 5 downregulation is associated with increased succinylation and activity of ACOX 1 and oxidative DNA damage response in hepatocellular carcinoma ( HCC ). Our study reveals a novel role of SIRT 5 in inhibiting peroxisome‐induced oxidative stress, in liver protection, and in suppressing HCC development.

CtBP1 and CtBP2 are closely related and evolutionarily conserved transcriptional corepressors. There is strong evidence linking CtBPs to tumorigenesis and tumor progression. CtBPs promote epithelial-mesenchymal transition and function as apoptosis antagonists. Also, CtBPs mediate repression of several tumor suppressor genes. Certain tumor suppressors also target CtBPs to restrain their tumor-promoting activity. Down-regulation of CtBPs mediated by some tumor suppressors results in p53-independent apoptosis and reduced tumor cell migration and invasion. The role of CtBPs in modulating the activities of different tumor suppressors is reviewed here. The results discussed here suggest that CtBPs may constitute a novel p53-independent anticancer target.