SIRT 5 inhibits peroxisomal ACOX 1 to prevent oxidative damage and is downregulated in liver cancer

Abstract

Peroxisomes account for ~35% of total HO generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of HO ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases HO production and oxidative DNA damage, which can be alleviated by knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

“…Additionally, patients with pathological grade II, a high clinical stage (III+IV), a TP53 mutation and those who received chemotherapy experienced improved OS, further indicating that increased SIRT3 expression predicts prolonged OS. SIRT5 has been reported to possess dual roles in the regulation of various types of carcinoma, suggesting that SIRT5 acts as a tumor suppressor in hepatic cancer by inhibiting acyl-CoA oxidase 1 (42). However, SIRT5 has also been demonstrated to function as an oncogene in the carcinogenesis of colorectal cancer (CRC), potentially by stimulating glutamine metabolism through the activation of dehydrogenase 1 during the tricarboxylic-acid cycle in CRC cells (43).…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…Moreover, the SIRT5 gene frequently shows an increase in duplication in specific cancer types, including uterine cancer, breast cancer, cutaneous and uveal melanomas, lung cancer, and lymphoma [150]. However, high SIRT5 expression is interrelated with a favorable prognosis for patients with HCC; the downregulation of SIRT5 is correlated with high ACOX1 succinylation and activity and poor survival in HCC patients [151]. Clearly, further studies are required to examine the possible involvement of SIRT5 in tumorigenesis.…”

HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer

“…In fact, dy-regulations of peroxisomal enzymes and/or their effects were shown in numerous tumor types including prostate cancer (Ko et al, 2018), colorectal carcinoma (Lakis et al, 2010), liver cancer (Lu et al, 2015;Chen et al, 2018), oral squamous cell carcinoma (Lai et al, 2018), pancreatic cancer (Deplanque et al, 2015), breast cancer (Keller et al, 1993), and lymphoma (Zheng et al, 2019). However, there was no systemic study of peroxisomes in lung cancer.…”