Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer

Abstract

Our review covers the recent epigenetic data that are focused on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of MMPs; TIMPs) and collagen substrates. Twenty-four MMPs, four TIMPs and at least 28 collagen types are known in humans. The MMP activity regulates the functionality of multiple extracellular matrix proteins, cytokines, growth factors and cell signaling and adhesion receptors. Aberrantly enhanced MMP proteolysis affects multiple cell functions, including proliferation, migration and invasion. This aberrant MMP proteolysis is frequently recorded in cancer. Recent evidence, however, indicates that several MMPs function as tumor suppressors in cancer. Their inhibition could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition and leading to adverse effects in cancer patients. The current epigenetic data suggest that there are distinct multi-layered epigenetic mechanisms that regulate MMPs, TIMPs and collagens. We show that in certain cancer types, epigenetic signatures of selected MMPs exhibit stem cell-like characteristics. Epigenetic mechanisms appear to play an especially important role in glioblastoma multiforme. Glioblastomas/gliomas synthesize de novo and then deposit collagens into the brain parenchyma. The collagen deposition, combined with an enhanced MMP activity in glioblastomas/gliomas, facilitates rapid invasion of tumor cells through the brain. It is tempting to hypothesize that the epigenetic mechanisms which control MMPs, TIMPs and collagens and, consequently, tumor cell invasion, represent promising drug targets and that in the near future these targets will be challenged pharmacologically.

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…Epigenetic mechanisms play a central role in regulating expression of MMPs in breast cancer, most notably MMP9 (46,47). We previously determined that hSETD1A-mediated H3K4me3 regulated MMP7 expression in colorectal cancer (26), compelling us to examine whether hSETD1A and corresponding H3K4me3 are recruited to MMP promoters for their expression in breast cancer cells.…”

Potential Roles of Protease Inhibitors in Cancer Progression

“…MMPs can be targeted by a growing number of miRNAs at posttranscriptional level, such as microRNA-146b, microRNA-29b and microRNA-10b (Fang et al, 2011). The methylation status of several MMP genes suppressed MMPs expression (Chernov and Strongin, 2011). The proteolytic activity and the expression of most MMPs are normally low in healthy tissues.…”

Effect of the Solvent Fractions of Zingiber officinale Roscoe against Thrombintreated Tumor Invasion in Human Oral Squamous Carcinoma YD-10B Cells

“…하지만 아직까지는 thrombin의 혈전형성에 대한 기전 은 정확하지 않다. 최근에는 암 침윤 및 전이과정에 있어 thrombin이 기질 금속단백분해효소(matrix metalloproteinases, MMPs)들과 혈소판과의 기능적인 상관관계가 있는 것으로 밝 혀지고 있다 [1,4,25]. 또한 종양세포에서 thrombin이 MMP-9 발현과 암세포 침윤 및 전이를 조절하는 것으로 보고하고 있 다 [5,11,12,24,28].…”