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

Yao, Jie1,2,3,4; Tang, Shuming3,5; Shi, Chenyan1,2,3; Lin, Yunzhi1,2,3; Ge, Lanlan1,2,3,6; Chen, Qinghua7; Ou, Baoru1,2,3; Liu, Dongyu1,2,3; Miao, Yuyang1,2,3; Xie, Qiujie1,2,3; Tang, Xudong8,9; Fei, Jia4; Yang, Guangyi7; Tian, Jun10; Zeng, Xiaobin1,2,3,5,11

2022-09-01

10.1080/15548627.2022.2119353

Autophagy   Impact Factor & Quartile

1554-8627

1554-8635

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.

Autophagy CDK6 hepatocellular carcinoma isoginkgetin GLUT1

SCI

English

Corresponding

National Natural Science Foundation of China["81503221","81903760","81903914"] ; Natural Science Foundation of Guangdong Province["2017A030313659","2021A1515110841","2021A1515220185"] ; Shenzhen Fundamental Research and Discipline Layout Project["JCYJ20170413093108233","JCYJ20190806151816859","JCYJ20210324113003007"] ; Sanming Project of Medicine in Shenzhen[SZZYSM202106004] ; Natural Science Foundation of Guangdong Province for Distinguished Young Scholars["2017A030313659","2021A1515220185"]

Cell Biology

Cell Biology

WOS:000853417600001

TAYLOR & FRANCIS INC

Web of Science

1.Jinan Univ, Ctr Lab, Longhua Branch, Shenzhen, Guangdong, Peoples R China
2.Jinan Univ, Shenzhen Peoples Hosp, Dept Infect Dis, Clin Med Coll 2, Shenzhen, Guangdong, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen, Guangdong, Peoples R China
4.Jinan Univ, Dept Biochem & Mol Biol, Med Coll, Guangzhou, Guangdong, Peoples R China
5.Jinan Univ, Shenzhen Peoples Hosp, Dept Clin Lab, Clin Med Coll 2, Shenzhen, Guangdong, Peoples R China
6.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Longhua Branch,Dept Pathol, Shenzhen, Guangdong, Peoples R China
7.Shenzhen Baoan Authent TCM Therapy Hosp, Dept Pharm, Shenzhen, Guangdong, Peoples R China
8.Tsinghua Univ, Key Lab New Drug Res TCM, Res Inst, Shenzhen, Guangdong, Peoples R China
9.Tsinghua Univ, Guangdong Innovat Chinese Med & Nat Med Engn Tech, Res Inst, Shenzhen, Guangdong, Peoples R China
10.Jiangsu Normal Univ, Coll Life Sci, Xuzhou, Jiangsu, Peoples R China
11.Shenzhen Univ, Guangdong Prov Key Lab Reg Immun & Dis, Med Sch, Shenzhen, Guangdong, Peoples R China

Yao, Jie,Tang, Shuming,Shi, Chenyan,et al. Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma[J]. Autophagy,2022.

Yao, Jie.,Tang, Shuming.,Shi, Chenyan.,Lin, Yunzhi.,Ge, Lanlan.,...&Zeng, Xiaobin.(2022).Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma.Autophagy.

Yao, Jie,et al."Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma".Autophagy (2022).