TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

Autor: Hao XL; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Lv YF; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Li DF; Clinical Medical Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China., Bai FH; Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China., Gong J; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Pan GQ; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Su LX; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Wang YL; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Fu WL; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Liu B; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Huang L; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Yan D; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Tan QL; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China., Liu JY; Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China. jinyiliutmmu@163.com., Guo QN; Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, People's Republic of China. qiaonan85@263.net.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Jan 02; Vol. 22 (1), pp. 6. Date of Electronic Publication: 2024 Jan 02.
DOI: 10.1186/s12967-023-04721-3
Abstrakt: Background: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood.
Methods: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays.
Results: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level.
Conclusions: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.
(© 2023. The Author(s).)
Databáze: MEDLINE
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