Abstract
HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non-small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1. Enforced accumulation of NPM1 oligomers by overexpression in weakly invasive but high HLJ1-expressing cells induced the activity of signal transducer and activator of transcription 3 (STAT3) and increased cellular migration, invasiveness, and colony formation. Furthermore, silencing HLJ1 accelerated NPM1 oligomerization, inhibited the activity of transcription corepressor activating enhancer binding protein 2alpha (AP-2alpha), and increased the activities of matrix metalloproteinase-2 (MMP-2) and STAT3. Our findings suggest that HLJ1 switches the role of NPM1, which can act as tumor suppressor or oncogene, by modulating the oligomerization of NPM1 via HLJ1-NPM1 heterodimer formation and recruiting AP-2alpha to the MMP-2 promoter.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Cell Nucleus / metabolism
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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HSP40 Heat-Shock Proteins / genetics
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HSP40 Heat-Shock Proteins / metabolism*
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HSP40 Heat-Shock Proteins / physiology
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Matrix Metalloproteinase 2 / genetics
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Multiprotein Complexes / metabolism
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Multiprotein Complexes / physiology
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Neoplasm Invasiveness
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism*
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Nuclear Proteins / physiology
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Nucleophosmin
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Protein Binding / genetics
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Protein Binding / physiology
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Protein Multimerization / genetics
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Protein Structure, Tertiary / physiology
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Protein Transport / genetics
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Transcription Factor AP-2 / metabolism
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Transcription Factor AP-2 / physiology*
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology
Substances
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DNAJB4 protein, human
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HSP40 Heat-Shock Proteins
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Multiprotein Complexes
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NPM1 protein, human
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Nuclear Proteins
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Transcription Factor AP-2
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Tumor Suppressor Proteins
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Nucleophosmin
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MMP2 protein, human
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Matrix Metalloproteinase 2