Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer

Yurou Chen, Yulong Qiang, Jiachen Fan, Qian Zheng, Leilei Yan, Guanlan Fan, Xiaofei Song, Nan Zhang, Qiongying Lv, Jiaqiang Xiong, Jingtao Wang, Jing Cao, Yanyan Liu, Jie Xiong (), Wei Zhang () and Feng Li ()
Additional contact information
Yurou Chen: Zhongnan Hospital of Wuhan University
Yulong Qiang: Wuhan University
Jiachen Fan: Wuhan University
Qian Zheng: Wuhan University
Leilei Yan: Wuhan University
Guanlan Fan: Zhongnan Hospital of Wuhan University
Xiaofei Song: Wuhan University
Nan Zhang: Wuhan University
Qiongying Lv: Zhongnan Hospital of Wuhan University
Jiaqiang Xiong: Zhongnan Hospital of Wuhan University
Jingtao Wang: Zhongnan Hospital of Wuhan University
Jing Cao: Zhongnan Hospital of Wuhan University
Yanyan Liu: Zhongnan Hospital of Wuhan University
Jie Xiong: Wuhan University
Wei Zhang: Zhongnan Hospital of Wuhan University
Feng Li: Zhongnan Hospital of Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1high ovarian cancer.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45698-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45698-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45698-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().