LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Abstract

Considerable evidences have shown that autophagy has an important role in tumor chemoresistance. However, it is still unknown whether the lncRNA HULC (highly upregulated in liver cancer) is involved in autophagy and chemoresistance of hepatocellular carcinoma (HCC). In this study, we for the first time demonstrated that treatment with antitumor reagents such as oxaliplatin, 5-fluorouracil and pirarubicin (THP) dramatically induced HULC expression and protective autophagy. Silencing of HULC sensitized HCC cells to the three antitumor reagents via inhibiting protective autophagy. Ectopic expression of HULC elicited the autophagy of HCC cells through stabilizing silent information regulator 1 (Sirt1) protein. The investigation for the corresponding mechanism by which HULC stabilized Sirt1 revealed that HULC upregulated ubiquitin-specific peptidase 22 (USP22), leading to the decrease of ubiquitin-mediated degradation of Sirt1 protein by removing the conjugated polyubiquitin chains from Sirt1. Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. In addition, we showed that the level of HULC was positively correlated with that of Sirt1 protein in human HCC tissues. Collectively, our data reveals that the pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents, suggesting that this pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

“…The importance of SIRT1 in hepatic autophagy regulation has been reported in ischemic livers (Biel et al., 2016), hepatocellular cancer (Xiong et al., 2017), and hepatosteatosis (Song et al., 2015). MFN2 plays a central role in autophagy induction in the liver (Biel et al., 2016), skeletal and cardiac muscle (Chen & Dorn, 2013; Sebastián et al., 2012).…”

The Lncrna-TUG1/EZH2 Axis Promotes Pancreatic Cancer Cell Proliferation, Migration and EMT Phenotype Formation Through Sponging Mir-382

“…LncRNAs have emerged as key regulators in cellular development and human diseases through modulating gene expression programs at transcriptional, post-transcriptional and epigenetic levels; for example, Koirala et al revealed that lncRNA AK023948 is a positive regulator of AKT; Xia et al demonstrated that lncRNA HOTAIR promotes metastasis of renal cell carcinoma by upregulating histone H3K27 demethylase JMJD3; Xiong H et al reported that lncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuated the chemosensitivity of HCC cells [16-18]. Targeting lncRNA-based signal pathways might be novel therapy method.…”

Identification of four prognostic LncRNAs for survival prediction of patients with hepatocellular carcinoma

“…In Panzitt’s et al (2007) study, lncRNA HULC , acting as a post-transcriptional regulator of gene expression, was detected to be highly specific up-regulation in HCC. Moreover, subsequent research has shown that HULC can trigger protective autophagy and attenuate the sensitivity of HCC cells to chemotherapeutic agents (Xiong et al, 2017). Among the four prognostic lncRNAs, RP11-150O12.3 was recognized as an independent predictor of gastric cancer (GC) prognosis (Ren et al, 2016), which also related to survival time of patients with colorectal adenocarcinoma (Zeng et al, 2017).…”