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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Adenovirus E1A Proteins / genetics
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Adenovirus E1A Proteins / metabolism*
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Animals
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Apoptosis
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Blotting, Western
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Breast Neoplasms / prevention & control*
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Cell Movement*
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Cell Proliferation
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E1A-Associated p300 Protein / genetics
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E1A-Associated p300 Protein / metabolism*
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Endoplasmic Reticulum Chaperone BiP
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Female
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Lung Neoplasms / metabolism
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary
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Mice
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Mice, SCID
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Protein Binding
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Protein Processing, Post-Translational
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Ubiquitination
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Xenograft Model Antitumor Assays
Substances
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Adenovirus E1A Proteins
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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RNA, Messenger
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E1A-Associated p300 Protein
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EP300 protein, human