4.7 Article

Epigenetic silencing of GCH1promotes hepatocellular carcinoma growth by activating superoxide anion-mediated ASK1/p38 signaling via inhibiting tetrahydrobiopterin de novo biosynthesis

期刊

FREE RADICAL BIOLOGY AND MEDICINE
卷 168, 期 -, 页码 81-94

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.03.025

关键词

GCH1; Tetrahydrobiopterin; ROS; Hepatocellular carcinoma; Metabolic reprogramming

资金

  1. National Natural Science Foundation of China [81701950]
  2. Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [KY2019Y002]
  3. Applied Basic Research Project of Sichuan Science and Technology Department [2018JY0276]
  4. Chengdu Science and Technology Innovation Research and Development Project [2018-YF05-01228-SN]

向作者/读者索取更多资源

The study reveals that epigenetic silencing of GCH1 promotes HCC growth by inhibiting BH4 de novo biosynthesis, while BH4 metabolite inhibits HCC growth.
Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). However, its role in HCC remains to be elucidated. Herein, we identified GTP cyclohydrolase 1 (GCH1), the first rate-limiting enzyme in tetrahydrobiopterin (BH4) de novo biosynthesis, as a novel metabolic regulator of HCC. GCH1 was frequently down-regulated in HCC tissues and cell lines by promoter methylation. Low GCH1 expression was associated with larger tumor size, increased tumor number, and worse prognosis in two independent cohorts of HCC patients. Functionally, GCH1 silencing promoted HCC growth in vitro and in vivo, while GCH1 overexpression exerted an opposite effect. The metabolite BH4 inhibited HCC growth in vitro and in vivo. GCH1 silencing exerted its growth-promoting effect through directly inhibiting BH4 de novo biosynthesis. Mechanistically, GCH1 silencing activated ASK1/p38 signaling; pharmacological or genetic inhibition of ASK1 or p38 abolished GCH1 silencing-induced growth-promoting effect. Further mechanistic studies found that GCH1 silencing-induced BH4 reduction resulted in an increase of intracellular superoxide anion levels in a dosedependent manner, which mediated the activation of ASK1/p38 signaling. Collectively, our study reveals that epigenetic silencing of GCH1 promotes HCC growth by activating superoxide anion-mediated ASK1/p38 signaling via inhibiting BH4 de novo biosynthesis, suggesting that targeting GCH1/BH4 pathway may be a promising therapeutic strategy to combat HCC.

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