2. Academic Validation
  3. ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis

ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis

  • Oncogenesis. 2020 Apr 29;9(4):42. doi: 10.1038/s41389-020-0226-z.
Junru Chen  # 1 2 3 4,  Chaofeng Ding  # 1 2 5,  Yunhao Chen  # 1 2 3 4,  Wendi Hu 1,  Yuejie Lu 1,  Wenxuan Wu 1,  Yanpeng Zhang 1 2 3 4,  Beng Yang 1 2 3 4,  Hao Wu 1 2 3 4,  Chuanhui Peng 1,  Haiyang Xie 2 3 4,  Lin Zhou 2 3 4,  Jian Wu 6 7 8,  Shusen Zheng 9 10 11 12 13
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China.
  • 2 NHC Key Laboratory of Combined Multi-organ Transplantation, 310003, Hangzhou, China.
  • 3 Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, 310003, Hangzhou, China.
  • 4 Key Laboratory of Organ Transplantation, 310003, Hangzhou, Zhejiang Province, China.
  • 5 Zhejiang Provincial Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, China.
  • 6 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China. drwujian@zju.edu.cn.
  • 7 Key Laboratory of Organ Transplantation, 310003, Hangzhou, Zhejiang Province, China. drwujian@zju.edu.cn.
  • 8 Zhejiang Provincial Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, China. drwujian@zju.edu.cn.
  • 9 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China. shusenzheng@zju.edu.cn.
  • 10 NHC Key Laboratory of Combined Multi-organ Transplantation, 310003, Hangzhou, China. shusenzheng@zju.edu.cn.
  • 11 Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, 310003, Hangzhou, China. shusenzheng@zju.edu.cn.
  • 12 Key Laboratory of Organ Transplantation, 310003, Hangzhou, Zhejiang Province, China. shusenzheng@zju.edu.cn.
  • 13 Zhejiang Provincial Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, China. shusenzheng@zju.edu.cn.
  • # Contributed equally.
PMID: 32350243 DOI: 10.1038/s41389-020-0226-z
Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. Long chain acyl-CoA synthetase 4 (ACSL4), an Enzyme has pivotal roles in arachidonic acid (AA) metabolism. However, its function and the underlying molecular mechanisms in HCC are still not fully elucidated. Here, we identified ACSL4 as a novel marker for AFP high subtype HCC through transcriptome profiling. ACSL4 was frequently upregulated in HCC samples and associated with poor prognosis. Functionally, ACSL4 knockdown resulted in decreased cell growth, whereas ectopic ACSL4 expression facilitated tumor formation in vitro and in vivo. Mechanistically, ACSL4 stabilized the oncoprotein c-Myc through ubiquitin-proteasome system in an ERK/FBW7-dependent manner. Cell growth ability mediated by ACSL4 elevation was partly attenuated by c-Myc depletion using siRNA or its inhibitor 10058-F4. In contrast, the effects of ACSL4 silencing were partially reversed by c-Myc overexpression via FBW7 knockdown. Clinically, ACSL4 expression was positively correlated with c-Myc in HCC. In conclusion, ACSL4 is a novel marker for AFP high subtype HCC. Our data uncovered a new mechanism by which ACSL4 promotes HCC progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis and could be a valuable prognostic biomarker and a potential therapeutic target in HCC.

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