Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells |
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Authors: | Minhu Chen Li Yang Guang Yang Yuan Li Hong Wang Guanjun Wang Wei Li Jiuwei Cui Jifan Hu |
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Affiliation: | 1. Division of Gastroenterology, First Affiliated Hospital, Sun Yat‐Sen University, Guangzhou, Guangdong, People's Republic of China;2. VA Palo Alto Health Care System, Stanford University Medical School, Palo Alto, CA, USA;3. Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, People's Republic of China |
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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. |
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Keywords: | cell reprogramming epigenetics epigenotype cancer DNA methylation histone modification MAPK signal pathway matrix metalloproteinases TIMPs |
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