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

被引：67

作者：

Cheng, X. ^{[1
,2
,3
]}

Yang, Y. ^{[1
,2
,4
]}

Fan, Z. ^{[1
,2
]}

Yu, L. ^{[1
,2
]}

Bai, H. ^{[1
,2
]}

Zhou, B. ^{[1
,2
]}

Wu, X. ^{[1
,2
]}

Xu, H. ^{[1
,2
]}

Fang, M. ^{[1
,2
,5
]}

Shen, A. ^{[6
]}

Chen, Q. ^{[1
,2
]}

Xu, Y. ^{[1
,2
]}

机构：

[1] Nanjing Med Univ, Key Lab Cardiovasc Dis, Nanjing 210029, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Dept Pathophysiol, Nanjing 210029, Jiangsu, Peoples R China

[3] Jiangsu Inst Nucl Med, Wuxi, Peoples R China

[4] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Jiangsu, Peoples R China

[5] Jiangsu Jiankang Vocat Univ, Dept Nursing, Nanjing, Jiangsu, Peoples R China

[6] Nantong Univ, Coll Med, Dept Key Lab Inflammat & Mol Targets, Nantong, Peoples R China

来源：

ONCOGENE | 2015年 / 34卷 / 44期

基金：

中国国家自然科学基金;

关键词：

PRO-INFLAMMATORY TRANSCRIPTION; BRAHMA-RELATED GENE-1; TGF-BETA; MRTF-A; MESENCHYMAL TRANSITION; LEUKEMIA; MATRIX-METALLOPROTEINASE-9; INDUCTION; CHROMATIN; REPRESSION;

D O I：

10.1038/onc.2015.14

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-beta), 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-beta, 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.

引用

页码：5570 / 5581

页数：12

共 65 条

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A novel real-time RT-PCR assay for quantification of OTT-MAL fusion transcript reliable for diagnosis of t(1;22) and minimal residual disease (MRD) detection [J].