USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway

Shuang Li; Lina Yang; Xiaoyan Ding; Hongxiao Sun; Xiaolei Dong; Fanghao Yang; Mengjun Wang; Huhu Zhang; Ya Li; Bing Li; Chunyan Liu

doi:10.1038/s41389-024-00528-z

USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway

Oncogenesis. 2024 Jul 19;13(1):27. doi: 10.1038/s41389-024-00528-z.

Authors

Shuang Li^#¹, Lina Yang^#¹, Xiaoyan Ding^{1

2}, Hongxiao Sun³, Xiaolei Dong¹, Fanghao Yang¹, Mengjun Wang¹, Huhu Zhang¹, Ya Li¹, Bing Li^{4

5}, Chunyan Liu⁶

Affiliations

¹ Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China.
² School of Basic Medicine, Institute of Stem Cell and Regenerative Medicine, Qingdao University, 266071, Qingdao, China.
³ Heart Center, Women and Children's Hospital, Qingdao University, 6 Tongfu Road, 266034, Qingdao, China.
⁴ Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China. libing_516@qdu.edu.cn.
⁵ Department of Dermatology, The Affiliated Haici Hospital of Qingdao University, 266000, Qingdao, China. libing_516@qdu.edu.cn.
⁶ Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, 266071, Qingdao, China. Liuchy@qdu.edu.cn.

^# Contributed equally.

Abstract

The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.