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TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer

Yuan-ming He1,2, Xiu-min Zhou3, Shuo-yi Jiang1,2, Zu-bin Zhang2, Bi-yin Cao2, Jin-bao Liu1, Yuan-ying Zeng4, Jun Zhao2,5, Xin-liang Mao1
1 Guangdong Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
2 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
3 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215106, China
4 Department of Oncology, Suzhou Municipal Hospital, Suzhou 215100, China
5 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215106, China
Correspondence to: Yuan-ying Zeng: zengyuanying@163.com, Jun Zhao: zhaojia0327@126.com, Xin-liang Mao: xinliangmao@gzhmu.edu.cn,
DOI: 10.1038/s41401-021-00662-z
Received: 21 December 2020
Accepted: 17 March 2021
Advance online: 30 April 2021

Abstract

The PTEN/AKT/mTOR signaling pathway is frequently dysregulated in non-small cell lung cancer (NSCLC), but the mechanisms are not well-understood. The present study found that the ubiquitin ligase TRIM25 is highly expressed in NSCLC tissues and promotes NSCLC cell survival and tumor growth. Mechanistic studies revealed that TRIM25 binds to PTEN and mediates its K63-linked ubiquitination at K266. This modification prevents the plasma membrane translocation of PTEN and reduces its phosphatase activity therefore accumulating PI(3,4,5)P3. TRIM25 thus activates the AKT/mTOR signaling. Moreover, we found that the antibacterial nitroxoline can activate PTEN by reducing its K63-linked polyubiquitination and sensitizes NSCLC to cisplatin-induced apoptosis. This study thus identified a novel modulation on the PTEN signaling pathway by TRIM25 and provides a potential target for NSCLC treatment.
Keywords: PTEN; TRIM25; K63-linked polyubiquitination; non-small cell lung cancer

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