PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2
Resource
Cell Cycle, 13(19), 3132-3142
Journal
Cell Cycle
Pages
3132-3142
Date Issued
2014
Date
2014
Author(s)
Kuo, Hong-Yi
Huang, Yen-Sung
Tseng, Chin-Hsiu
Chen, Yi-Chen
Chang, Yu-Wei
Shih, Hsiu-Ming
Wu, Cheng-Wen
Abstract
Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon- (IFN) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFN induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2.
Subjects
ATRS
Interferon-
lung adenocarcinoma
MMP2
nuclear EGFR
PML
STAT3
promyelocytic leukemia protein
EGFR
EGF receptor
LAC
nEGFR
matrix metalloprotease-2
AT-rich sequence
IFN
interferon-
INM
inner nuclear membrane
SDGs
Other Subjects
beta interferon; epidermal growth factor receptor; gelatinase A; promyelocytic leukemia protein; STAT3 protein; beta interferon; cyclin D1; epidermal growth factor; epidermal growth factor receptor; gelatinase A; histone; nuclear protein; PML protein, human; small interfering RNA; STAT3 protein; transcription factor; tumor suppressor protein; animal experiment; animal model; Article; AT rich sequence; cancer inhibition; controlled study; enzyme activation; gene repression; histone acetylation; human; human cell; lung cancer; lung cancer cell line; metastasis; mouse; nonhuman; promoter region; protein analysis; protein expression; tumor invasion; upregulation; adenocarcinoma; animal; antagonists and inhibitors; binding site; cell nucleus; drug effects; genetics; HEK293 cell line; lung tumor; male; metabolism; metastasis; nonobese diabetic mouse; nucleotide sequence; pathology; SCID mouse; transcription initiation; tumor cell line; Adenocarcinoma; Animals; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Nucleus; Cyclin D1; Epidermal Growth Factor; HEK293 Cells; Histones; Humans; Interferon-beta; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Nuclear Proteins; Promoter Regions, Genetic; Receptor, Epidermal Growth Factor; RNA, Small Interfering; STAT3 Transcription Factor; Transcription Factors; Transcriptional Activation; Tumor Suppressor Proteins; Up-Regulation