PRAME Augments K63-Linked Ubiquitination and Stabilization of METTL3 to Promote Lung Adenocarcinoma Metastasis.
10 affiliations
- 1Department of Laboratory Medicine and Institute of Precise Medicine, The First Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China.
- 2Zhongshan School of Medicine Sun Yat-Sen University Guangzhou Guangdong China.
- 3Cancer Institute, School of Basic Medical Sciences Southern Medical University Guangzhou Guangdong China.
- 4Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research Jiangmen Central Hospital Jiangmen Guangdong China.
- 5Department of Neurosurgery Jiangmen Central Hospital Jiangmen Guangdong China.
- 6Sun Yat-sen University Cancer Center Guangzhou Guangdong China.
- 7Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China.
- 8State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences University of Macau Macau SAR China.
- 9Department of Endocrinology and Diabetes Center, The First Affiliated Hospital Sun Yat-sen University Guangzhou China.
- 10State Key Laboratory of Multi-Organ Injury Prevention and Treatment Southern Medical University Guangzhou Guangdong China.
Abstract
Metastasis is the primary cause of mortality in cancer including lung adenocarcinoma (LUAD), yet the underlying mechanisms remain incompletely understood. Preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen, displays context-dependent functions across malignancies, but its biological role in LUAD metastasis has not been clearly defined. Here, we demonstrate that the significantly upregulated PRAME in metastatic LUAD directly interacts with the m⁶A methyltransferase METTL3 and promotes its K63-linked non-proteolytic ubiquitination. This modification occurs at lysine 235 of METTL3, increases its protein stability and facilitates METTL3 interaction with METTL14 and WTAP. Consequently, m⁶A modification of TGFB2 mRNA and activation of the TGF-β signaling pathway are enhanced, which is essential for PRAME-driven pro-metastatic effects both in vitro and in vivo. Clinically, PRAME expression positively correlates with METTL3 protein abundance and TGF-β pathway activation, and is robustly associated with poor clinical outcomes. Taken together, our findings identify K63-linked ubiquitination as a previously unrecognized post-translational modification of METTL3 and underscore the importance of the PRAME/METTL3/TGF-β axis in LUAD metastasis, providing mechanistic insights and potential therapeutic targets for this malignancy.
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BibTeX
@article{yang2026prame,
title = {{PRAME Augments K63-Linked Ubiquitination and Stabilization of METTL3 to Promote Lung Adenocarcinoma Metastasis.}},
author = {Xia Yang and Xuemei Xu and Yaxuan Zhang and Jiamei Guo and Zhiyu Ye and Qiaorui Bai and Xiuqiao Yang and Shujun Liang and Xiang Dong and Xin Zhang and Jiyong Gu and Shuqin Dai and Hongchun Du and Meiwan Chen and Tianyu Tao and Hongyu Guan and Jueheng Wu and Han Tian and Junchao Cai and Mengfeng Li and Xu Li and Yi Yang},
journal = {MedComm},
year = {2026},
month = oct,
doi = {10.1002/mco2.71066},
url = {https://europepmc.org/article/MED/42899254},
note = {CC BY},
}
RIS
TY - JOUR
TI - PRAME Augments K63-Linked Ubiquitination and Stabilization of METTL3 to Promote Lung Adenocarcinoma Metastasis.
AU - Xia Yang
AU - Xuemei Xu
AU - Yaxuan Zhang
AU - Jiamei Guo
AU - Zhiyu Ye
AU - Qiaorui Bai
AU - Xiuqiao Yang
AU - Shujun Liang
AU - Xiang Dong
AU - Xin Zhang
AU - Jiyong Gu
AU - Shuqin Dai
AU - Hongchun Du
AU - Meiwan Chen
AU - Tianyu Tao
AU - Hongyu Guan
AU - Jueheng Wu
AU - Han Tian
AU - Junchao Cai
AU - Mengfeng Li
AU - Xu Li
AU - Yi Yang
PY - 2026
DA - 2026/10/19
JO - MedComm
DO - 10.1002/mco2.71066
UR - https://europepmc.org/article/MED/42899254
AB - Metastasis is the primary cause of mortality in cancer including lung adenocarcinoma (LUAD), yet the underlying mechanisms remain incompletely understood. Preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen, displays context-dependent functions across malignancies, but its biological role in LUAD metastasis has not been clearly defined. Here, we demonstrate that the significantly upregulated PRAME in metastatic LUAD directly interacts with the m⁶A methyltransferase METTL3 and promotes its K63-linked non-proteolytic ubiquitination. This modification occurs at lysine 235 of METTL3, increases its protein stability and facilitates METTL3 interaction with METTL14 and WTAP. Consequently, m⁶A modification of TGFB2 mRNA and activation of the TGF-β signaling pathway are enhanced, which is essential for PRAME-driven pro-metastatic effects both in vitro and in vivo. Clinically, PRAME expression positively correlates with METTL3 protein abundance and TGF-β pathway activation, and is robustly associated with poor clinical outcomes. Taken together, our findings identify K63-linked ubiquitination as a previously unrecognized post-translational modification of METTL3 and underscore the importance of the PRAME/METTL3/TGF-β axis in LUAD metastasis, providing mechanistic insights and potential therapeutic targets for this malignancy.
SN - 2688-2663
ER -