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De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells.

ABSTRACT: Elevated expression of heat shock protein 5 (HSPA5) promotes drug resistance and metastasis and is a marker of poor prognosis in breast cancer patients. Adenovirus type 5 E1A gene therapy has demonstrated antitumor efficacy but the mechanisms of metastasis-inhibition are unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination by GP78 (E3 ubiquitin ligase) and subsequent proteasome-mediated degradation. Our findings point out the Ying-Yang regulation of two different post-translational modifications (ubiquitination and acetylation) of HSPA5 in tumor metastasis.

SUBMITTER: Chang YW

PROVIDER: S-EPMC4279393 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells.

Chang Yi-Wen YW Chen Hsin-An HA Tseng Chi-Feng CF Hong Chih-Chen CC Ma Jui-Ti JT Hung Mien-Chie MC Wu Chih-Hsiung CH Huang Ming-Te MT Su Jen-Liang JL

Oncotarget 20141101 21

Elevated expression of heat shock protein 5 (HSPA5) promotes drug resistance and metastasis and is a marker of poor prognosis in breast cancer patients. Adenovirus type 5 E1A gene therapy has demonstrated antitumor efficacy but the mechanisms of metastasis-inhibition are unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination by GP78 (E3 ubiquitin ligase) and subsequent p ...[more]

PMID: 25301734

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Project description:BackgroundIn prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology.MethodsAcetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection.ResultsAcetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin.ConclusionPGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy.

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De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells.

Publications

De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells.

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