Frontiers in oncology · 2026
Type I collagen promotes triple-negative breast cancer progression through a UBE2V1-ACSL5 regulatory axis.
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Liu Lu, Wang Yida, You Haiyue, Wang Cenzhu, Yang Xinfeng, Zhang Feng, Wu Danping, Ning Xin, Qian Zhiwen, Jiang Ying, Zhang Yan, Zhao Xiaoqian, Han Tingting
Аннотация
INTRODUCTION: Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and extensive extracellular-matrix remodeling. Type I collagen (COL I), a major stromal component, promotes tumor progression, but the downstream tumor-cell mechanisms remain incompletely defined. We investigated whether COL I regulates acyl-CoA synthetase long-chain family member 5 (ACSL5) through ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) and whether this relationship contributes to malignant behavior.
METHODS: We integrated public-dataset analyses, transcriptome sequencing, and in vitro functional and biochemical assays. MDA-MB-231 and BT-549 cells were exposed to COL I, with ACSL5 overexpression or UBE2V1 knockdown as indicated. ACSL5 expression and stability were assessed by qPCR, western blotting, CHX-chase analysis, CQ or MG132 treatment, ubiquitination assays, immunoprecipitation-mass spectrometry, and co-immunoprecipitation.
RESULTS: COL I enhanced proliferation, colony formation, migration, and invasion and reduced ACSL5 protein abundance in both TNBC cell lines. ACSL5 overexpression partially reversed these malignant phenotypes. COL I did not significantly alter ACSL5 mRNA expression by qPCR but accelerated ACSL5 protein loss; MG132, but not chloroquine, partially restored ACSL5, and total ACSL5 ubiquitination increased after COL I treatment. Immunoprecipitation-mass spectrometry and co-immunoprecipitation identified UBE2V1 as an ACSL5-associated protein whose expression and association with ACSL5 were enhanced by COL I. UBE2V1 knockdown partially restored ACSL5 protein expression and significantly attenuated COL I-induced migration and invasion. Public-dataset analyses further showed reduced ACSL5 expression in breast cancer and associations between ACSL5 and immune-infiltration features; these observations were exploratory and were not supported by direct immune-functional assays.
DISCUSSION: These findings identify a COL I-UBE2V1-ACSL5 regulatory relationship that contributes to TNBC malignant progression. The data support UBE2V1-associated regulation of proteasome-sensitive ACSL5 loss, while the complete ubiquitination machinery and the in vivo, clinical, and immune relevance remain to be defined.
METHODS: We integrated public-dataset analyses, transcriptome sequencing, and in vitro functional and biochemical assays. MDA-MB-231 and BT-549 cells were exposed to COL I, with ACSL5 overexpression or UBE2V1 knockdown as indicated. ACSL5 expression and stability were assessed by qPCR, western blotting, CHX-chase analysis, CQ or MG132 treatment, ubiquitination assays, immunoprecipitation-mass spectrometry, and co-immunoprecipitation.
RESULTS: COL I enhanced proliferation, colony formation, migration, and invasion and reduced ACSL5 protein abundance in both TNBC cell lines. ACSL5 overexpression partially reversed these malignant phenotypes. COL I did not significantly alter ACSL5 mRNA expression by qPCR but accelerated ACSL5 protein loss; MG132, but not chloroquine, partially restored ACSL5, and total ACSL5 ubiquitination increased after COL I treatment. Immunoprecipitation-mass spectrometry and co-immunoprecipitation identified UBE2V1 as an ACSL5-associated protein whose expression and association with ACSL5 were enhanced by COL I. UBE2V1 knockdown partially restored ACSL5 protein expression and significantly attenuated COL I-induced migration and invasion. Public-dataset analyses further showed reduced ACSL5 expression in breast cancer and associations between ACSL5 and immune-infiltration features; these observations were exploratory and were not supported by direct immune-functional assays.
DISCUSSION: These findings identify a COL I-UBE2V1-ACSL5 regulatory relationship that contributes to TNBC malignant progression. The data support UBE2V1-associated regulation of proteasome-sensitive ACSL5 loss, while the complete ubiquitination machinery and the in vivo, clinical, and immune relevance remain to be defined.