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
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GYS2/p53 负反馈环路限制 HBV 相关肝细胞癌中的肿瘤生长。
DOI：
10.1158/0008-5472.can-18-2357
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发表时间：
2019-02-01
期刊：
影响因子：
11.2
通讯作者：
Yun, Jing-Ping
中科院分区：
文献类型：
--
作者：
Chen, Shi-Lu;Zhang, Chris Zhiyi;Yun, Jing-Ping
肝细胞癌的发生是由于代谢相关基因调控改变导致细胞代谢重编程。阐明肝细胞癌代谢异常的机制，为肝细胞癌的治疗提供新的靶点具有重要的意义。在此，我们证明了糖原合成酶2（GYS 2）通过与p53的负反馈环限制了B型肝炎病毒相关的肝癌的肿瘤生长。GYS 2的表达在HCC中显著下调，并且与糖原含量降低和不利的患者预后相关。GYS 2过表达抑制，而GYS 2敲低通过调节p53表达促进体外细胞增殖和体内肿瘤生长。GYS 2与MDM 2竞争性结合以防止p53被MDM 2介导的泛素化和降解。此外，GYS 2增强了p300诱导的p53在K373/382处的乙酰化，这反过来又抑制了GYS 2在HBx/HDAC 1复合物支持下的转录。总之，我们的研究结果表明，GYS 2作为一个预后因子，并作为一个肿瘤抑制剂在肝癌的功能。新发现的HBx/GYS 2/p53轴负责糖原代谢的失调，并为HCC的临床管理代表了一个有前途的治疗靶点。意义：我们阐明了HBx/GYS 2/p53轴的临床意义、生物学功能和调节，补充了对肿瘤糖原代谢的理解，并为HCC治疗提供了潜在的预后和治疗靶点。[图形]。
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.[GRAPHICS].