2. Academic Validation
  3. Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma

Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma

  • Autophagy. 2022 Sep 13;1-18. doi: 10.1080/15548627.2022.2119353.
Jie Yao 1 2,  Shuming Tang 3,  Chenyan Shi 1,  Yunzhi Lin 1,  Lanlan Ge 1 4,  Qinghua Chen 5,  Baoru Ou 1,  Dongyu Liu 1,  Yuyang Miao 1,  Qiujie Xie 1,  Xudong Tang 6,  Jia Fei 2,  Guangyi Yang 5,  Jun Tian 7,  Xiaobin Zeng 1 3 8
Affiliations

Affiliations

  • 1 Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 2 Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou, Guangdong, China.
  • 3 Department of Clinical Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 4 Department of pathology(Longhua Branch), Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 5 Department of Pharmacy, Shenzhen Baoan Authentic TCM Therapy Hospital, Shenzhen, Guangdong, China.
  • 6 Key Lab for New Drug Research of TCM and Guangdong Innovative Chinese Medicine and Natural Medicine Engineering Technology Research Center, Research Institute of Tsinghua University, Shenzhen, Guangdong, China.
  • 7 College of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.
  • 8 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Medicine School of Shenzhen University, Shenzhen, Guangdong, China.
PMID: 36048765 DOI: 10.1080/15548627.2022.2119353
Abstract

Isoginkgetin (ISO), a natural biflavonoid, exhibited cytotoxic activity against several types of Cancer cells. However, its effects on hepatocellular carcinoma (HCC) cells and mechanism remain unclear. Here, we revealed that ISO effectively inhibited HCC cell proliferation and migration in vitro. LC3-II expression and autophagosomes were increased under ISO treatment. In addition, ISO-induced cell death was attenuated by treatment with chloroquine or knockdown of autophagy-related genes (ATG5 or ULK1). ISO significantly suppressed SLC2A1/GLUT1 (solute carrier family 2 member 1) expression and glucose uptake, leading to activation of the AMPK-ULK1 axis in HepG2 cells. Overexpression of SLC2A1/GLUT1 abrogated ISO-induced Autophagy. Combining molecular docking with thermal shift analysis, we confirmed that ISO directly bound to the N terminus of CDK6 (cyclin-dependent kinase 6) and promoted its degradation. Overexpression of CDK6 abrogated ISO-induced inhibition of SLC2A1/GLUT1 transcription and induction of Autophagy. Furthermore, ISO treatment significantly decreased the H3K27ac, H4K8ac and H3K4me1 levels on the SLC2A1/GLUT1 enhancer in HepG2 cells. Finally, ISO suppressed the hepatocarcinogenesis in the HepG2 xenograft mice and the diethylnitrosamine+carbon tetrachloride (DEN+CCl4)-induced primary HCC mice and we confirmed SLC2A1/GLUT1 and CDK6 as promising oncogenes in HCC by analysis of TCGA data and human HCC tissues. Our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1, resulting in decreased glucose levels and inducing the AMPK-ULK1 pathway.

Keywords

Autophagy; CDK6; SLC2A1/GLUT1; hepatocellular carcinoma; isoginkgetin.

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