SKP2 Promotes Hepatocellular Carcinoma Progression Through Nuclear AMPK-SKP2-CARM1 Signaling Transcriptionally Regulating Nutrient-Deprived Autophagy Induction

Abstract

Background/Aims: SKP2 overexpression has been associated with poor prognosis in numerous cancers. The mechanisms of autophagy in the tumor pathogenesis have been a research focus recently. How the SKP2 involved in autophagy expresses oncogenic characteristics, especially in HCC, are largely unclear. Methods: The expression of SKP2 was detected by qPCR, Western blot, Immunohistochemical (IHC) and Immunofluorescence (IF) techniques. SKP2 was knocked down or overexpressed by lentivirus transfection in HCC cells. Functional assays such as CCK8 assays, transwell migration and invasion assays, and colony formation assays were performed to determine the role of SKP2 in HCC. Furthermore, autophagy was induced by glucose deprivation in HCC cells followed by monitoring of the levels and distributions of SKP2, CARM1 and AMPK. Results: Our data showed that SKP2 levels were significantly increased in HCC cell lines and HCC tissues rather than corresponding normal liver tissues, and augmented SKP2 levels were statistically correlated with tumor grade, size and metastases. By up-regulation or down-regulation of SKP2 in HCC cells, we confirmed that SKP2 encourages proliferation, migration, invasion, and colony formation. We then found that SKP2 was inhibited, CARM1 increased and AMPKα2 became activated in the nucleus under glucose deprivation induced autophagy. Moreover, we discovered that SKP2 was repressing CARM1 in the nucleus under nutrient-sufficient conditions in HCC. Conclusions: We show that SKP2 promotes HCC progression and its nuclear functions of autophagy induction with CARM1 and AMPK, which may provide a potential target for HCC therapy.

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

“…Nuclear inclusions in hepatocellular carcinoma correlate with survival nuclear AMPK-SKP2-CARM1 signalling was also reported in HCC autophagy [41].…”

“…Intriguingly, studies of Shin et al showed that co‐activator‐associated arginine methyltransferase 1 (CARM1)‐dependent histone arginine methylation is a crucial nuclear event in autophagy . Induction by nuclear AMPK‐SKP2‐CARM1 signalling was also reported in HCC autophagy .…”

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

“…Skp2 has been demonstrated to enhance tumor progression and development via the regulation of various biological processes, namely cell proliferation, the cell cycle, apoptosis, invasion and metastasis (4)(5)(6). In liver cancer, the expression of Skp2 is associated with histological grade and tumor size, suggesting that Skp2 may be a prognostic biomarker for patients with liver cancer (7,8). A recent study demonstrated that Skp2 promoted the proliferation, colony formation, migration and invasion of liver cancer cells (8).…”

“…In liver cancer, the expression of Skp2 is associated with histological grade and tumor size, suggesting that Skp2 may be a prognostic biomarker for patients with liver cancer (7,8). A recent study demonstrated that Skp2 promoted the proliferation, colony formation, migration and invasion of liver cancer cells (8). Therefore, Skp2 may be a potential target in the treatment of liver cancer.…”

Skp2 modulates proliferation, senescence and tumorigenesis of glioma

“…An increase in p27 Kip1 has been found to significantly reduce Mixed-Lineage Leukemia self-renewal ability, promote the monocytic differentiation of leukemic blasts, and induce cell death [5]. Skp2 has shown important roles in the development and progression of tumors as it was found to be frequently overexpressed in various human malignancies like hepatocellular carcinoma, breast cancer, lung cancers, prostate cancer, and osteosarcoma [2,[6][7][8][9][10][11]. In hepatocellular carcinoma, Skp2 was identified at a significantly increased level compared with paired normal tissue, and was correlated with tumor grade, size, and metastases.…”