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Caveolin-1 facilitated KCNA5 expression, promoting breast cancer viability.

ABSTRACT: Potassium voltage-gated channel subfamily A member 5 (KCNA5) is a voltage-gated potassium channel protein encoded by the KCNA5 gene. A large number of studies have shown that KCNA5 is associated with the survival of malignant tumors, including breast cancer, but the detailed mechanism remains inconclusive. Our previous study found that KCNA5 is co-expressed with a scaffolding protein, caveolin-1 in MCF-10A-neoT non-tumorigenic epithelial cell. In the present study, KCNA5 and caveolin-1 were expressed in breast cancer tissues and cell lines. Exposing MCF-10A-neoT to 2 mM of methyl-?-cyclodextrin, an agent to disrupt caveolae and lipid rafts led to a downregulation of caveolin-1 that reduced the expression of KCNA5. Furthermore, following caveolin-1 knockdown, the expression of KCNA5 was decreased in MDA-MB-231 human breast cancer and MCF-10A-neoT non-tumorigenic epithelial cell lines. In subsequent experiments, the MTT assay showed that increased caveolin-1 and KCNA5 expression promoted the survival of MCF-7 human breast cancer cells, but cell survival was not affected following KCNA5 overexpression alone. Using small interfering RNA technology, KCNA5-silenced MCF-10A-neoT cells were established and a decreased level of phosphorylated-AKT serine/threonine kinase (AKT) was observed in the cells compared with the parental cells. Overall, these results suggested that caveolin-1 facilitated KCNA5 expression and may be associated with AKT activation.

SUBMITTER: Qu C

PROVIDER: S-EPMC6144920 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Caveolin-1 facilitated KCNA5 expression, promoting breast cancer viability.

Qu Chao C Sun Jia J Liu Ying Y Wang Xiaobo X Wang Lifen L Han Chao C Chen Qian Q Guan Tianhui T Li Hongyan H Zhang Yejun Y Wang Yang Y Liu Jia J Zou Wei W Liu Jing J

Oncology letters 20180803 4

Potassium voltage-gated channel subfamily A member 5 (KCNA5) is a voltage-gated potassium channel protein encoded by the <i>KCNA5</i> gene. A large number of studies have shown that KCNA5 is associated with the survival of malignant tumors, including breast cancer, but the detailed mechanism remains inconclusive. Our previous study found that KCNA5 is co-expressed with a scaffolding protein, caveolin-1 in MCF-10A-neoT non-tumorigenic epithelial cell. In the present study, KCNA5 and caveolin-1 we ...[more]

PMID: 30250548

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Project description:Caveolin-1 (Cav1) is an integral membrane, scaffolding protein found in plasma membrane invaginations (caveolae). Cav1 regulates multiple cancer-associated processes. In breast cancer, a tumor suppressive role for Cav1 has been suggested; however, Cav1 is frequently overexpressed in aggressive breast cancer subtypes, suggesting an oncogenic function in advanced-stage disease. To further delineate Cav1 function in breast cancer progression, we evaluated its expression levels among a panel of cell lines representing a spectrum of breast cancer phenotypes. In basal-like (the most aggressive BC subtype) breast cancer cells, Cav1 was consistently upregulated, and positively correlated with increased cell proliferation, anchorage-independent growth, and migration and invasion. To identify mechanisms of Cav1 gene regulation, we compared DNA methylation levels within promoter 'CpG islands' (CGIs) with 'CGI shores', recently described regions that flank CGIs with less CG-density. Integration of genome-wide DNA methylation profiles ('methylomes') with Cav1 expression in 30 breast cancer cell lines showed that differential methylation of CGI shores, but not CGIs, significantly regulated Cav1 expression. In breast cancer cell lines having low Cav1 expression (despite promoter CGI hypomethylation), we found that treatment with a DNA methyltransferase inhibitor induced Cav1 expression via CGI shore demethylation. In addition, further methylome assessments revealed that breast cancer aggressiveness associated with Cav1 CGI shore methylation levels, with shore hypermethylation in minimally aggressive, luminal breast cancer cells and shore hypomethylation in highly aggressive, basal-like cells. Cav1 CGI shore methylation was also observed in human breast tumors, and overall survival rates of breast cancer patients lacking estrogen receptor ? (ER?) negatively correlated with Cav1 expression. Based on this first study of Cav1 (a potential oncogene) CGI shore methylation, we suggest this phenomenon may represent a new prognostic marker for ER?-negative, basal-like breast cancer.

Project description:Objectives: CD44, a transmembrane glycoprotein, is involved in the generation of a stem cell niche and maintaining stem cell quiescence. The aim of this study was to evaluate its contribution to ovarian cancer prognosis and progression, as well as explore the possible mechanisms. Materials and Methods: The expression of CD44 in tissue microarray of 90 ovarian cancer patients was detected by immunohistochemistry. Kaplan-Meier method and Cox proportional hazard model were used to evaluate the factors associated with 5-year overall survival and disease-free survival. CD44 was knocked down by small interfering RNA, the expression of Snail, ZEB1, and Caveolin-1 in a stable Snail-expressing ovarian cancer cell line HO8910PM-Snail (HOPM-Snail) and its control cell line HO8910PM-vector (HOPM) was detected by western blotting analysis. Cell clone formation, migration, and invasion of HOPM-Snail and HOPM cells with CD44 silencing were examined by 3-D culture assay, wound healing assay, and transwell assay, respectively. Results: Over-expression of CD44 was associated with advanced histological grade (p = 0.014) and FIGO stage (p = 0.001). Multivariate analysis showed that CD44 expression was an independent prognostic factor to predict both overall survival (p = 0.004) and disease-free survival (p = 0.025) of ovarian cancer patients. Down-regulation of CD44 expression by small silencing RNA abrogated both basal Snail expression and TGF-β1-induced Snail expression in HOPM and HOPM-Snail cells. In addition, CD44 knockdown caused a decrease in ZEB1 expression. RPPA data indicated that Caveolin-1 may be another regulative target of CD44, and western blotting analysis confirmed that CD44 knockdown caused an increase in Caveolin-1 expression. However, there was no noticeable reciprocal regulation among ZEB1, Caveolin-1, and Snail. Moreover, CD44 knockdown caused a decrease in cell clone formation, migration, and invasion of HOPM and HOPM-Snail cells. Conclusions: As both Snail and ZEB1 are crucial inducers of epithelial-to-mesenchymal transition (EMT), our data suggested that CD44 may be crucial for the EMT process of ovarian cancer. Therefore, CD44 may be a potential prognostic marker as well as treatment target for ovarian cancer.

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Caveolin-1 facilitated KCNA5 expression, promoting breast cancer viability.

Publications

Caveolin-1 facilitated KCNA5 expression, promoting breast cancer viability.

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