SIRT5 promotes cell proliferation and invasion in hepatocellular carcinoma by targeting E2F1

Abstract

Sirtuin 5 (SIRT5) is a member of the NAD+‑dependent class III protein deacetylases. Although it is known that SIRT5 deacetylates and activates urate oxidase in the liver mitochondria of mice, the mechanism of SIRT5 in the proliferation of hepatocellular carcinoma (HCC) remains to be fully elucidated. The present study investigated the expression and functional significance of SIRT5 in HCC, and examined the relevant mechanism. SIRT5 was found to be upregulated in HCC tissues and cell lines, and the higher expression of SIRT5 indicated poorer overall survival. Reverse transcription‑quantitative polymerase chain reaction analysis, western blot analysis, chromatin immunoprecipitation analysis, and luciferase reporter gene, proliferation and Transwell assays were performed to elucidate the function of SIRT5 in the regulation of cell proliferation and invasion in human HCC. Functionally, it was observed that the inhibition of SIRT5 significantly suppressed HCC cell proliferation and invasion, whereas the overexpression of SIRT5 promoted HCC cell proliferation and invasion in vitro. E2F transcription factor 1 (E2F1) was identified as a novel target gene of SIRT5. In addition, the knockdown of SIRT5 induced the expression of E2F1, and the knockdown of E2F1 in HCC cells partially reversed the effect of SIRT5 in promoting cell proliferation and invasion. Collectively, these data provide the first evidence, to the best of our knowledge, that the SIRT5 gene has an important regulatory role in liver carcinogenesis, and may function as a novel potential therapeutic target for HCC.

The Roles of Sirtuin Family Proteins in Cancer Progression

“…SIRT5 contributes to cell invasion in HCC by targeting E2F1 [65]. Additionally, targeting SIRT5 enables miR-299-3p to inhibit the migration and invasion of HCC cells [69].…”

“…Only a limited amount of research has been conducted on SIRT5 in tumorigenesis. Several recent studies have shown that SIRT5 may play a tumor-promoting role in multiple types of cancer, such as HCC [65], colon cancer [63], human osteosarcoma [63] and breast cancer [149]. 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].…”

Increased Expression Together with the Gene Regulation Network of NEIL3 Predicts Poor Prognosis and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

“…Among the TFs targeted by NEIL3, E2F1 represents a key link in the cell cycle regulation network, and its aberrant expression participates in HCC occurrence and development, which also predicts the unfavorable patient prognosis [42]. As reported, E2F1, which is tightly linked to cell division cycle associated 5 (CDCA5), Sirtuin 5 (SIRT5) and other important molecules, may serve as a vital anti-apoptotic factor in liver cancer due to its ability to offset c-Myc-driven apoptosis [43,44]. As suggested in previous literature, the repressive complex, which includes the component of E2F4, is relieved by CDK upon reentry into the cell cycle; thereafter, E2F1-Sp1, which is in the form of complex E2F1-NF-Y, can be recruited to the promoter [45].…”

Multi-omics Prognostic Analysis of Lysine Acetylation Regulators in Glioma

“…SIRT5 functions both as a lysine acetyltransferase, and as a desuccinylase, demalonylase, or deglutarylase [26][27][28]. Although several reports have indicated that SIRT5 can act as an oncogene in different cancers [29][30][31][32], SIRT5 downregulation has also been associated with poor prognosis in glioblastoma patients [33].…”