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Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells

Authors :
Ji-Fan Hu
Bihui Zhong
Yuan Li
Andrew R. Hoffman
Guanjun Wang
Li Yang
Hong Wang
Wei Li
Guang Yang
Minhu Chen
Shenghong Zhang
Jiuwei Cui
Source :
International Journal of Cancer. 134:1583-1594
Publication Year :
2013
Publisher :
Wiley, 2013.

Abstract

Cancer progression is characterized by extensive tumor invasion into the surrounding extracellular matrix (ECM) and migration to metastatic sites. The increased proteolytic degradation of the ECM during tumor invasion is directly dependent on the activity of matrix metalloproteinases (MMPs), counter-balanced by tissue inhibitors of matrix metalloproteinases (TIMPs). In this study, we found that unbalanced expression of MMP/TIMP axis genes in tumors was correlated with aberrant epigenotypes in the various gene promoters. The malignant epigenotypes could be therapeutically corrected by a simple defined factor-mediated reprogramming approach. Correction of the abnormal epigenotypes by nuclear remodeling leads to a rebalance in the gene expression profile, an alteration in tumor cell morphology, attenuation of tumor cell migration and invasion in vitro, and reduced tumorigenicity in nude mice. We further identified the downregulation of the MKK-p38 MAPK signal pathway as an important underlying mechanism for reduced tumorigenicity in this epigenetic reprogramming model. These data demonstrate that the malignant phenotypes seen in cancer can be corrected by a nuclear remodeling mechanism, thus highlighting a novel non-chemotherapeutic, non-radiotherapeutic approach for the treatment of cancer.

Details

ISSN :
00207136
Volume :
134
Database :
OpenAIRE
Journal :
International Journal of Cancer
Accession number :
edsair.doi...........fd32f78fb39435554a01c3dcc1fb5a01
Full Text :
https://doi.org/10.1002/ijc.28487