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 factormediated 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.

A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies

“…For qPCR, cDNA samples were amplified using CFX96 TM real-time system (BIO-RAD) by SYBR PrimeScript™ RT-PCR Kit (TaKaRa) (35). The mRNA expression level of IRAIN and IGF1R was quantitated by normalizing with β-actin (housekeeping gene) as previously described (34,36).…”

Targeted gene suppression by inducing de novo DNA methylation in the gene promoter

“…Genomic DNA was extracted and treated with sodium bisulfite (Sigma, Missouri, United States) as previously described [48-50]. The CMV promoter region was amplified with three primer sets.…”

Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

“…The amplification was composed of 1 cycle at 95°C for 5 min, 33 cycles at 95°C for 20s, 62°C for 15 s and 72°C for 15 s, and 1 cycle at 72°C for 10 min. Results were normalized to the internal control β-Actin [40,41].…”