Publication Date
6-1-2024
Journal
PLoS Biology
DOI
10.1371/journal.pbio.3002666
PMID
38905316
PMCID
PMC11192366
PubMedCentral® Posted Date
6-21-2024
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Animals, Female, Humans, Mice, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glycolysis, Histones, L-Lactate Dehydrogenase, Lactate Dehydrogenase 5, Mice, Inbred BALB C, Mice, Nude, Neoplasm Invasiveness, Neoplasm Metastasis, Potassium Channels, Tandem Pore Domain, Prognosis, Up-Regulation
Abstract
Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.
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