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

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.

• Authors: Shenghong Zhang, Bihui Zhong, Minhu Chen, Li Yang, Guang Yang, Yuan Li, Hong Wang, Guanjun Wang, Wei Li, Jiuwei Cui, Andrew R Hoffman, Jifan Hu
• Journal: International journal of cancer (Int J Cancer) Vol. 134 Issue 7 Pg. 1583-94 (Apr 01 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24105737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013 UICC.

Chemical References

• Tissue Inhibitor of Metalloproteinases
• p38 Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases
• Matrix Metalloproteinases

Topics

• Carcinogenesis (genetics)
• Cell Growth Processes (genetics)
• Cell Line
• Cell Line, Tumor
• Cell Movement (genetics)
• Down-Regulation
• Epigenesis, Genetic
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• MAP Kinase Signaling System
• Matrix Metalloproteinases (biosynthesis, genetics)
• Mitogen-Activated Protein Kinase Kinases (genetics)
• Neoplasm Invasiveness
• Signal Transduction
• Stomach Neoplasms (genetics, metabolism, pathology)
• Tissue Inhibitor of Metalloproteinases (biosynthesis, genetics)
• Transcriptome
• p38 Mitogen-Activated Protein Kinases (genetics)