SIRT1‐mediated transcriptional regulation of SOX2 is important for self‐renewal of liver cancer stem cells

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Histone deacetylatase sirtuin 1 (SIRT1) has been shown to be up-regulated in human cancers; however, its role in liver CSCs is unknown. In this study, we explored the biological functions of SIRT1 in liver CSCs. Our data show that SIRT1 is highly expressed in liver CSCs and decreases during differentiation. In addition, high levels of SIRT1 predict a decreased probability of survival in patients with HCC. SIRT1 is responsible for the maintenance of self-renewal and tumorigenicity of liver CSCs, and overexpression of exogenous SIRT1 can restore self-renewal of non-CSCs. We demonstrated that SOX2 is a main downstream regulator of SIRT1-mediated self-renewal and tumorigenicity potential of liver CSCs. Mechanistically, SIRT1 regulates transcription of the SOX2 gene by way of chromatin-based epigenetic changes, which are dependent on DNA methylation. This effect is achieved by alternation of histone modification and interaction with DNA methyltransferase 3A, resulting in hypermethylation of SOX2 promoter. Furthermore, we demonstrated that insulin growth factor signaling plays an important role in maintaining SIRT1 expression through increased SIRT1 protein stability. Conclusions: These findings highlight the importance of SIRT1 in the biology of liver CSCs and suggest that SIRT1 may serve as a molecular target for HCC therapy. (HEPATOLOGY 2016;64:814-827)

A Transforming Growth Factor‐β and H19 Signaling Axis in Tumor‐Initiating Hepatocytes That Regulates Hepatic Carcinogenesis

“…These observations are further corroborated by patient‐based studies that Sox2 is the most increased gene among core pluripotency factors in premalignant cirrhotic liver, where hepatocytes have already become resistant to TGFβ‐induced mitoinhibition/apoptosis . In addition to being considered as a predictor for poor survival of HCC patients, Sox2 has also been shown to play an essential role in self‐renewal and maintenance of cancer stem‐like cell populations in HCC . Therefore, TGF‐β signaling may counterbalance Sox2 in cancer initiating and progenitor cell differentiation.…”

“…(40) In addition to being considered as a predictor for poor survival of HCC patients, (41) Sox2 has also been shown to play an essential role in self-renewal and maintenance of cancer stem-like cell populations in HCC. (42) Therefore, TGF-β signaling may counterbalance Sox2 in cancer initiating and progenitor cell differentiation.…”

miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

“…It plays important roles in cell proliferation, apoptosis, aging, inflammation and metabolism (30–32). In addition, it can affect tumorigenesis, development and metastasis of a tumor (33,34). Sirt1 is heterogeneously expressed in tumor, which is closely related to tumor types.…”

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

“…More interestingly, the suppressive effects of SOX2 on HBV RNA transcription and HBV protein production are also confirmed in the BALB/c mice sera and liver tissues. We suggested that SOX2 may act as a restriction factor to repress HBV replication, not only during the acute infection, but also in the chronic infection and the development of liver diseases [12,20]. Previous studies have reported that HBV mRNA was lower in the HCC tissues relative to the non-tumor liver tissues [21,22].…”

“…SOX2 is also involved in the progression of HCC. For instance, SOX2 is a main downstream regulator of the silent information regulator 1 (SIRT1)-mediated self-renewal and tumorigenicity of liver cancer stem cells [12]. Moreover, overexpression of SOX2 and its co-factor Oct4 can be novel predictors of poor prognosis for patients undergoing resection of HCC [10].…”