TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

F Yin,Y Peng,G Sharen,H Wei,R Chen,W Jing,B Li,J Zhao,F Yuan,X Zhou

doi:10.1038/oncsis.2017.49

Abstract

Lipid reprogramming has been considered as a crucial characteristic in hepatocellular carcinoma (HCC) initiation and progression. However, detailed molecular mechanisms have yet to be clearly defined. Here, we examined the effects of tumor suppressor TIP30 on the regulation of HCC lipid metabolism. We found that decreased TIP30 expression leads to elevated fatty acid synthesis and enhanced levels of lipogenic enzymes SCD and FASN in HCC cells. Moreover, SREBP1 is one of the key transcription factors regulating liver lipid metabolism, and TIP30 deficiency significantly increased SREBP1 expression and nuclear accumulation. Small interfering RNAs targeting SREBP1 could reverse fatty acid synthesis induced by TIP30 deficiency. Furthermore, downregulating TIP30 activated the Akt/mTOR signaling pathway to upregulate SREBP1 expression, which promoted lipid metabolism by activating gene transcription of lipogenesis, including fasn and scd. We also showed that TIP30 deficiency-regulated lipid metabolism promoted proliferation of HCC cells. Clinically, our data revealed that TIP30 expression significantly correlated with SREBP1 in patients with HCC and that a combination of TIP30 and SREBP1 is a powerful predictor of HCC prognosis. Together, our data suggested a novel function of TIP30 in HCC progression and indicate that TIP30 regulation of SREBP1 may represent a novel target for HCC treatment.

Highlights

The morbidity and mortality of hepatocellular carcinoma (HCC)ranks top[5] and top[3] respectively among common malignant tumors worldwide
To determine whether TIP30 regulates lipid metabolism of HCC cells, microarray analysis was firstly applied for comparing gene expression profiles of HCC-LM3 infected with shNon or shTip30. 837 genes were differentially expressed upon TIP30 knockdown
The results indicated that genes that significantly the Akt/mTOR signaling pathway correlated to TIP30 expression were involved in fatty acid metabolism (Supplementary Figure 1A), which suggested the important role of TIP30 involved in lipid metabolism regulation

Summary

Introduction

Ranks top[5] and top[3] respectively among common malignant tumors worldwide. Major risk factors of HCC are viral hepatitis, exposure to hepatotoxins and alcohol abuse, whereas recent clinic and epidemiology researches indicate nonalcoholic fatty liver disease (NAFLD) increases HCC incidence.[3] Recently, metabolic reprogramming, especially lipid metabolism alteration, is considered to be the initiating factor of tumor occurrence and progression. Continuous de novo cholesterogenesis and lipogenesis are frequently activated in tumors for providing extra lipids and lipid precursors during rapid cell proliferation.[4] Several key enzymes have been identified to promote de novo lipid synthesis, including fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD) and acetyl-CoA carboxylase (ACC).[5] detailed mechanisms of abnormal lipid metabolism have not yet been comprehensively identified during HCC progression

Methods

Results

Conclusion