OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1
Abstract Immunotherapy has made a breakthrough in triple negative breast cancer (TNBC). The aim of this study is to investigate the specific role and regulatory mechanism of 3-oxoacid CoA-transferase 1 (OXCT1) in influencing TNBC growth and immune escape induced by aerobic glycolysis. OXCT1-induced...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08433-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761460104724480 |
|---|---|
| author | Hongchen Zhang Min Ling Yuheng Zhang Qing Fang Wanlong Wo Xiaoai Lv |
| author_facet | Hongchen Zhang Min Ling Yuheng Zhang Qing Fang Wanlong Wo Xiaoai Lv |
| author_sort | Hongchen Zhang |
| collection | DOAJ |
| description | Abstract Immunotherapy has made a breakthrough in triple negative breast cancer (TNBC). The aim of this study is to investigate the specific role and regulatory mechanism of 3-oxoacid CoA-transferase 1 (OXCT1) in influencing TNBC growth and immune escape induced by aerobic glycolysis. OXCT1-induced enhancement of TNBC cell proliferation and PD-L1 expression is reversed by 2-DG. After interference with OXCT1 in TNBC patient-derived organoids (PDOs), tumor cell proliferation and lactic acid secretion are attenuated, and T-cell killing is enhanced. OXCT1 correlates with phosphoglycerate kinase 1 (PGK1) protein expression in clinical TNBC samples. In vitro overexpression of OXCT1 has no significant effect on PGK1 mRNA expression, but increases the succinylation level of PGK1 K146 and its protein stability, while decreasing its ubiquitination. The H4K20me1 level in the OXCT1 promoter region is increased in TNBC tissues, and in vitro lysine methyltransferase 5 A (KMT5A) overexpression increases the H4K20me1 level in the OXCT1 promoter region to promote OXCT1 expression. In conclusion, OXCT1 interference reverses the KMT5A-induced enhancement of TNBC cell viability, proliferation, and PD-L1 expression. KMT5A promotes OXCT1 expression through histone methylation, and OXCT1 increases PGK1 protein stability through succinylation modification, thereby promoting aerobic glycolysis and immune escape in TNBC. |
| format | Article |
| id | doaj-art-4b4fb18daba04d2489c8f150fe777f3a |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-4b4fb18daba04d2489c8f150fe777f3a2025-08-20T03:06:01ZengNature PortfolioCommunications Biology2399-36422025-07-018111210.1038/s42003-025-08433-wOXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1Hongchen Zhang0Min Ling1Yuheng Zhang2Qing Fang3Wanlong Wo4Xiaoai Lv5Department of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Department of General Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)The First School of Clinical Medicine, Zhejiang Chinese Medical UniversityThe First School of Clinical Medicine, Zhejiang Chinese Medical UniversityThe First School of Clinical Medicine, Zhejiang Chinese Medical UniversityDepartment of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)Abstract Immunotherapy has made a breakthrough in triple negative breast cancer (TNBC). The aim of this study is to investigate the specific role and regulatory mechanism of 3-oxoacid CoA-transferase 1 (OXCT1) in influencing TNBC growth and immune escape induced by aerobic glycolysis. OXCT1-induced enhancement of TNBC cell proliferation and PD-L1 expression is reversed by 2-DG. After interference with OXCT1 in TNBC patient-derived organoids (PDOs), tumor cell proliferation and lactic acid secretion are attenuated, and T-cell killing is enhanced. OXCT1 correlates with phosphoglycerate kinase 1 (PGK1) protein expression in clinical TNBC samples. In vitro overexpression of OXCT1 has no significant effect on PGK1 mRNA expression, but increases the succinylation level of PGK1 K146 and its protein stability, while decreasing its ubiquitination. The H4K20me1 level in the OXCT1 promoter region is increased in TNBC tissues, and in vitro lysine methyltransferase 5 A (KMT5A) overexpression increases the H4K20me1 level in the OXCT1 promoter region to promote OXCT1 expression. In conclusion, OXCT1 interference reverses the KMT5A-induced enhancement of TNBC cell viability, proliferation, and PD-L1 expression. KMT5A promotes OXCT1 expression through histone methylation, and OXCT1 increases PGK1 protein stability through succinylation modification, thereby promoting aerobic glycolysis and immune escape in TNBC.https://doi.org/10.1038/s42003-025-08433-w |
| spellingShingle | Hongchen Zhang Min Ling Yuheng Zhang Qing Fang Wanlong Wo Xiaoai Lv OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 Communications Biology |
| title | OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 |
| title_full | OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 |
| title_fullStr | OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 |
| title_full_unstemmed | OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 |
| title_short | OXCT1 promotes triple negative breast cancer immune escape via modulating succinylation modification of PGK1 |
| title_sort | oxct1 promotes triple negative breast cancer immune escape via modulating succinylation modification of pgk1 |
| url | https://doi.org/10.1038/s42003-025-08433-w |
| work_keys_str_mv | AT hongchenzhang oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 AT minling oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 AT yuhengzhang oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 AT qingfang oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 AT wanlongwo oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 AT xiaoailv oxct1promotestriplenegativebreastcancerimmuneescapeviamodulatingsuccinylationmodificationofpgk1 |