1. Academic Validation
  2. A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma

A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma

  • Cancer Res. 2019 Feb 1;79(3):534-545. doi: 10.1158/0008-5472.CAN-18-2357.
Shi-Lu Chen  # 1 2 Chris Zhiyi Zhang  # 1 2 Li-Li Liu  # 1 2 Shi-Xun Lu 1 2 Ying-Hua Pan 3 Chun-Hua Wang 1 2 Yang-Fan He 1 2 Cen-Shan Lin 1 2 Xia Yang 1 2 Dan Xie 1 2 Jing-Ping Yun 4 2
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. yunjp@sysucc.org.cn.
  • # Contributed equally.
Abstract

Hepatocellular carcinogenesis is attributed to the reprogramming of cellular metabolism as a consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in hepatitis B virus-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC. SIGNIFICANCE: We elucidated the clinical significance, biological function, and regulation of the HBx/GYS2/p53 axis, which supplement the understanding of tumor glycogen metabolism and provide potential prognostic and therapeutic targets for HCC treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/534/F1.large.jpg.

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