Ubiquitin specific peptidase 38 epigenetically regulates KLF transcription factor 5 to augment malignant progression of lung adenocarcinoma

Protein ubiquitination is a common post-translational modification and a critical mechanism for regulating protein stability. This study aimed to explore the role and potential molecular mechanism of ubiquitin-specific peptidase 38 (USP38) in the progression of lung adenocarcinoma (LUAD). USP38 expr...

Full description

Saved in:

Bibliographic Details
Published in:	Oncogene Vol. 43; no. 16; pp. 1190 - 1202
Main Authors:	Zhang, Tao, Su, Fei, Wang, Bofang, Liu, Lixin, Lu, Yongbin, Su, Hongxin, Ling, Ruijiang, Yue, Peng, Dai, Huanyu, Yang, Tianning, Yang, Jingru, Chen, Rui, Wu, Ruiyue, Zhu, Kaili, Zhao, Da, Hou, Xiaoming
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 12-04-2024 Nature Publishing Group
Subjects:	13/105 13/51 13/89 14/35 38/89 45 631/67/1612/1350 631/67/2324 64/60 692/53/2422 82/58 82/80 Adenocarcinoma Animal models Apoptosis Cancer Cell Biology Cell culture Cell proliferation Human Genetics Internal Medicine Krueppel-like factor Lung cancer Medicine Medicine & Public Health Molecular modelling Oncology Post-translation Proteins SUMO protein Transcription factors Ubiquitin Ubiquitination
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Protein ubiquitination is a common post-translational modification and a critical mechanism for regulating protein stability. This study aimed to explore the role and potential molecular mechanism of ubiquitin-specific peptidase 38 (USP38) in the progression of lung adenocarcinoma (LUAD). USP38 expression was significantly higher in patients with LUAD than in their counterparts, and higher USP38 expression was closely associated with a worse prognosis. USP38 silencing suppresses the proliferation of LUAD cells in vitro and impedes the tumorigenic activity of cells in xenograft mouse models in vivo. Further, we found that USP38 affected the protein stability of transcription factor Krüppel-like factors 5 (KLF5) by inhibiting its degradation. Subsequent mechanistic investigations showed that the N-terminal of USP38 (residues 1-400aa) interacted with residues 1-200aa of KLF5, thereby stabilizing the KLF5 protein by deubiquitination. Moreover, we found that PIAS1-mediated SUMOylation of USP38 was promoted, whereas SENP2-mediated de-SUMOylation of USP38 suppressed the deubiquitination effects of USP38 on KLF5. Additionally, our results demonstrated that KLF5 overexpression restored the suppression of the malignant properties of LUAD cells by USP38 knockdown. SUMOylation of USP38 enhances the deubiquitination and stability of KLF5, thereby augmenting the malignant progression of LUAD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-024-02985-7