Full Text | PDF

Int J Biol Sci 2024; 20(5):1744-1762. doi:10.7150/ijbs.86658 This issue Cite

Research Paper

The m6A modification-mediated positive feedback between glycolytic lncRNA SLC2A1-DT and c-Myc promotes tumorigenesis of hepatocellular carcinoma

Zhu Zeng^1#, Jie Wang^1#, Fengyu Xu^1#, Ping Hu^1#, Yuhang Hu¹, Wenfeng Zhuo¹, Ding Chen¹, Shengbo Han¹, Fan Wang¹, Yong Zhao¹, Yan Huang¹, Gang Zhao^1,2✉

1. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2. Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
# These authors contributed equally to the paper as first authors.

✉ Corresponding author: Professor Gang Zhao: gangzhaoedu.cn, Phone number: +86-02785726829, Fax: 027-85726935, Address: Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No. 1277, Wuhan, Hubei Province, China. More

Abstract

Glycolysis exerts a key role in the metabolic reprogramming of cancer. Specific long non-coding RNAs (lncRNAs) have been identified to exhibit oncogenic glycolysis regulation. Nevertheless, the precise mechanisms by which glycolysis-related lncRNAs control hepatocellular carcinoma (HCC) are still unknown. We profiled and analyzed glycolysis-associated lncRNA signatures using HCC specimens from The Cancer Genome Atlas (TCGA) dataset. Considerable upregulation of the glycolysis-related lncRNA SLC2A1-DT was noted in HCC tissues; this upregulation was strongly linked with advanced tumor stage and poor prognosis. Cell culture and animal-related studies indicated that knockdown or overexpression of SLC2A1-DT obviously restrained or promoted glycolysis, propagation, and metastasis in HCC cells. Mechanistically, SLC2A1-DT enhanced the interaction of protein between β-catenin and YWHAZ, suppressing the binding between β-catenin and β-TrCP, an E3 ubiquitin ligase. Thereby, SLC2A1-DT impeded the β-TrCP-dependent ubiquitination and β-catenin degradation. The upregulated β-catenin activated the transcription of c-Myc, which then increased the transcription of glycolytic genes including SLC2A1, LDHA, and HK2. Additionally, we revealed that c-Myc transcriptionally induced the expression of methyltransferase 3 (METTL3), which increased N6-methyladenosine (m6A) modification and stability of SLC2A1-DT in a YTHDF1 dependent manner. Collectively, we show that the lncRNA SLC2A1-DT promotes glycolysis and HCC tumorigenesis by a m6A modification-mediated positive feedback mechanism with glycolytic regulator c-Myc and suggested as an innovative treatment option and indicator for HCC.

Keywords: Hepatocellular carcinoma, m6A modification, SLC2A1-DT, β-catenin, c-Myc, Glycolysis.

Citation styles

©2024 Ivyspring International Publisher. Terms of use