Hepatocellular Carcinoma‐Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element‐Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Increased lipogenesis has been reported to play a critical role in HCC progression. However, the underlying mechanism contributing to lipogenesis increase in HCC remains elusive. Here, we show that HCC-associated protein TD26 (TD26) was highly expressed in HCC tumor tissues compared to matched normal tissues. From the clinicopathologic analyses of two independent HCC cohorts, we demonstrate that TD26 expression was positively correlated with tumor size and was an independent predictor of overall survival (OS) and recurrence-free survival (RFS) in HCC patients. Our metabolomics assays demonstrate that TD26 had no effect on glycometabolism, but significantly increased lipogenesis in HCC cells. In addition, our functional assays indicate that TD26 promoted HCC cell proliferation and tumor growth. We further demonstrate that TD26-mediated increase in lipogenesis and tumor cell proliferation was SREBP1 dependent. Mechanistically, we demonstrate that, through its C-terminus (amino acids [aa] from 121 to 198), TD26 interacted with the truncated nuclear sterol regulatory element-binding protein 1 (SREBP1) form (nSREBP1), but not full-length SREBP1 (flSREBP1), to block adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mediated inhibition on SREBP1 activity, resulting in increased lipogenesis, elevated tumor cell proliferation, and enhanced tumor progression. Conclusion: We propose that TD26 is a positive regulator on SREBP1 transactivity, and the interaction between TD26 and SREBP1 can serve as a potential therapeutic target for HCC treatment.

ZHX2 inhibits SREBP1c‐mediated de novo lipogenesis in hepatocellular carcinoma via miR‐24‐3p

“…As the main regulator of hepatic lipogenesis, SREBP1c is highly expressed in HCC cells [13]. SREBP1c mainly transactivates expression of the fatty acid synthesis genes FASN, ACC1, ACL, and SCD1, which also were found elevated in HCC [4,[9][10][11]13]. In the present study, we found that ZHX2 inhibited SREBP1c expression in HCC cell lines and was negatively associated with SREBP1c in HCC tissues.…”

“…The key DNL enzymes FASN, ACC1, ACL, and SCD1 are transcriptionally regulated by SREBP1, which is highly expressed in many types of tumors including HCC [4,[9][10][11]13]. We then elucidated whether ZHX2 regulates SREBP1c, the hepatic isoform of SREBP1 [12].…”

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

“…ANGPTL8 was significantly overexpressed in HCC, and ANGPTL8 positively correlated with the tumor size in HCC [55]. Lipogenesis and proliferation in HCC are also increased by ANGPTL8 through interaction with nuclear SREPBP-1 [55]. Altogether, ANGPTL profiling in NASH patients could identify patients at risk of HCC but further evaluation in larger studies is required.…”

“…ANGPTL4 expression was lower in HCC tissue than non-tumorous liver tissue [65] and full-length ANGPTL4-overexpression in mice suppressed HCC tumorigenesis and metastasis [65]. ANGPTL8 was significantly overexpressed in HCC, and ANGPTL8 positively correlated with the tumor size in HCC [55]. Lipogenesis and proliferation in HCC are also increased by ANGPTL8 through interaction with nuclear SREPBP-1 [55].…”

“…ANGPTL8/betatrophin (also known as HCC associated protein, TD26, or lipasin) [54,55] is expressed primarily in liver and visceral adipose tissue (VAT), and is associated with liver steatosis and increased plasma triglyceride levels in humans [55,56]. Serum levels of ANGPTL8 are significantly increased in IR [57] and T2DM [58,59].…”