ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer | Cancer Research | American Association for Cancer Research

Authors

• Hao Liu, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Hui Lyu, LSU Health Sciences Center - New OrleansFollow
• Guanmin Jiang, Sun Yat-sen University, Zhuhai, Gungdong, CN
• Danyang Cheng, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Sanbao Ruan, Stanley S. Scott Cancer Center, New Orleans, LA
• Shuang Liu, Stanley S. Scott Cancer Center, New Orleans, LA
• Lukun Zhou, Stanley S. Scott Cancer Center, New Orleans, LA
• Minqiang Yang, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Shanshan Zeng, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Zhimin He, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Hongsheng Wang, Sun Yat-sen University, Zhuhai, Gungdong, CN
• Hongsheng Liu, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Guopei Zheng, Guangzhou Medical University, Guangzhou, Guangdong, CN
• Bolin Liu, LSU Health Sciences Center - New OrleansFollow

Document Type

Article

Publication Date

11-2-2022

Publication Title

Cancer Research

Abstract

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry–based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies.

First Page

3974

Last Page

3986

Volume

82

Issue

21

Publisher

American Association for Cancer Research

Rights

©2022 American Association for Cancer Research

Recommended Citation

Liu, Hao; Lyu, Hui; Jiang, Guanmin; Cheng, Danyang; Ruan, Sanbao; Liu, Shuang; Zhou, Lukun; Yang, Minqiang; Zeng, Shanshan; He, Zhimin; Wang, Hongsheng; Liu, Hongsheng; Zheng, Guopei; and Liu, Bolin, "ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer | Cancer Research | American Association for Cancer Research" (2022). School of Medicine Faculty Publications. 4529.
https://digitalscholar.lsuhsc.edu/som_facpubs/4529
10.1158/0008-5472.CAN-22-0800