MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription.

Abstract:

:Malignant tumors are exemplified by excessive proliferation and aggressive migration/invasion contributing to increased mortality of cancer patients. Matrix metalloproteinase 9 (MMP9) expression is positively correlated with lung cancer malignancy. The mechanism underlying an elevated MMP9 expression is not clearly defined. We demonstrate here that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) was activated by hypoxia and transforming growth factor (TGF-β), two prominent pro-malignancy factors, in cultured lung cancer cells. MKL1 levels were also increased in more invasive types of lung cancer in humans. Depletion of MKL1 in lung cancer cells attenuated migration and invasion both in vitro and in vivo. Overexpression of MKL1 potentiated the induction of MMP9 transcription by hypoxia and TGF-β, whereas MKL1 silencing diminished MMP9 expression. Of interest, MKL1 knockdown eliminated histone H3K4 methylation surrounding the MMP9 promoter. Further analyses revealed that MKL1 recruited ASH2, a component of the H3K4 methyltransferase complex, to activate MMP9 transcription. Depletion of ASH2 ameliorated cancer cell migration and invasion in an MMP9-dependent manner. Together our data indicate that MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription.

journal_name

Oncogene

journal_title

Oncogene

authors

Cheng X,Yang Y,Fan Z,Yu L,Bai H,Zhou B,Wu X,Xu H,Fang M,Shen A,Chen Q,Xu Y

doi

10.1038/onc.2015.14

subject

Has Abstract

pub_date

2015-10-29 00:00:00

pages

5570-81

issue

44

eissn

0950-9232

issn

1476-5594

pii

onc201514

journal_volume

34

pub_type

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