Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation.
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.
Chang
Tzu-Pei
TP
Institutes of Biomedical Sciences and Molecular Biology, National Chung Hsing University, Taiwan 40227,ROC.
Yu
Sung-Liang
SL
Lin
Sheng-Yi
SY
Hsiao
Yi-Jing
YJ
Chang
Gee-Chen
GC
Yang
Pan-Chyr
PC
Chen
Jeremy J W
JJ
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000090243:Nucleophosmin; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D055503:Protein Multimerization / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
C494650:DNAJB4 protein, human; D050956:HSP40 Heat-Shock Proteins; D046912:Multiprotein Complexes; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2