METTL14-mediated m6A modification enhances USP22-ERα axis to drive breast cancer malignancy

Xuefen Zhuang; Shusha Yin; Ji Cheng; Wenshuang Sun; Zesen Fang; Yujie Xiang; E-Ying Peng; Yu Yao; Yuting Li; Xiaoyue He; Li Lu; Yuanfei Deng; Hongbiao Huang; Gengxi Cai; Yuning Liao

doi:10.1016/j.phrs.2024.107509

METTL14-mediated m⁶A modification enhances USP22-ERα axis to drive breast cancer malignancy

Pharmacol Res. 2024 Nov 17:210:107509. doi: 10.1016/j.phrs.2024.107509. Online ahead of print.

Authors

Xuefen Zhuang¹, Shusha Yin¹, Ji Cheng¹, Wenshuang Sun¹, Zesen Fang², Yujie Xiang³, E-Ying Peng³, Yu Yao³, Yuting Li³, Xiaoyue He³, Li Lu⁴, Yuanfei Deng⁵, Hongbiao Huang⁶, Gengxi Cai⁷, Yuning Liao⁸

Affiliations

¹ Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
² KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China.
³ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
⁴ School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
⁵ Department of Pathology, The First People's Hospital of Foshan, Foshan 528000, China.
⁶ Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: huanghongbiao@gzhmu.edu.cn.
⁷ Department of Breast Surgery, The First People's Hospital of Foshan, Foshan 528000, China. Electronic address: caigengxi@126.com.
⁸ Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: liaoyuningm1@126.com.

PMID: 39557350
DOI: 10.1016/j.phrs.2024.107509

Abstract

The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m⁶A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m⁶A modification. YTHDC1 and YTHDF1 function as readers for m⁶A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα⁺ BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.

Keywords: Breast cancer; ERα; M(6)A; METTL14; USP22.