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

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC.

Zinc fingers and homeoboxes 2 is required for diethylnitrosamine‐induced liver tumor formation in C57BL/6 mice

“…Previous studies using hepatoma cell lines indicated that increased Zhx2 expression resulted in reduced cell proliferation in vitro and reduced xenograft growth in nude mice [ 21 ] and that HTVI of oncogenes AKT/Myc led to more tumors in Zhx2 liver‐knockout mice, [ 22 ] consistent with Zhx2 functioning as a tumor suppressor. To explore the role of Zhx2 in the initiation and progression of tumor development in vivo , we used the well‐established DEN model in Zhx2 wt and Zhx2 KO mice.…”

“…[ 19 , 20 ] Tissue culture and xenograft studies using human hepatoma cell lines indicated that Zhx2 inhibits cell proliferation and reduces levels of cyclins A and E, [ 21 ] supporting the possibility that Zhx2 functions as a tumor suppressor. Liver‐specific Zhx2 knockout mice had increased tumors compared with wild‐type controls after hydrodynamic tail‐vein injection (HTVI) of the oncogenes AKT and Myc, [ 22 ] consistent with tumor suppressor activity of Zhx2.…”

Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

“…As an HCC-associated tumor suppressor, zinc fingers and homeoboxes 2 (ZHX2) is negatively associated with SREBP-1c in HCC cell lines and human specimens. ZHX2 can increase miRNA-24-3p at the transcription level to induce SREBP-1c degradation for the suppression of HCC progression ( 94 ). A member of the acyl-CoA synthetase (ACS) family, acyl CoA synthetase 4 (ACSL4) has been identified as an oncogene and a novel marker of alpha-fetoprotein-high subtype HCC.…”

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

“…SREBP-1 is a transcriptional factor and plays a pivotal role in the proliferation and metastasis of liver cancer cells by regulating fatty acid synthesis and [81] and suppressing liver inflammation [82]. Other factors, such as long-chain acyl CoA synthetase 4 (ACSL4) [83], caveolin-1 (Cav1) [84], and zinc fingers and homeoboxes 2 (ZHX2) [85], can regulate lipid metabolism via the SREBP1 signaling pathway. Lipid metabolism is correlated tightly with glucose metabolism in HCC.…”