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PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2.


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.

SUBMITTER: Kuo HY 

PROVIDER: S-EPMC4614437 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2.

Kuo Hong-Yi HY   Huang Yen-Sung YS   Tseng Chin-Hsiu CH   Chen Yi-Chen YC   Chang Yu-Wei YW   Shih Hsiu-Ming HM   Wu Cheng-Wen CW  

Cell cycle (Georgetown, Tex.) 20140101 19


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 translocat  ...[more]

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