Targeting Abnormal Methylation Enzymes: A New Approach to Cancer Therapy

The objective of this article is to promote abnormal methylation enzymes (MEs) as a critical cause of cancer and the destabilization of abnormal MEs as a new approach to direct cancer therapy. MEs are a ternary enzyme complex consisting methionine adenosyltransferase (MAT)-methylatransferase (MT)-S-adenostkhomocysteine hydrolase (SAHH) which plays a pivotal role on the regulation of cell grow and differentiation. Normal cell growth is under the allosteric regulation of MEs by steroid hormone. In telomerase expressing cells such as pluripotent stem cells, MEs become associated with telomerase that changes kinetic properties of MAT-SAHH isozyme pair by increasing Km values and the regulation greatly in favor of cell growth. Embryonic development of the fetus depends on abnormal MEs to regulate exceptional growth. Abnormal MEs do not cause problem to cells expressing telomerase, because the operation of abnormal MEs is strictly under the control of safety mechanisms such as contact inhibition, ten-eleven translocator-1 enzyme and chemo-surveillance. If safety mechanisms become dysfunctional, clinical symptoms will arise, cancer being the worst case. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs) which are pluripotent embryonic stem cells. Wound unhealing is mostly attributable to the collapse of chemo-surveillance. But the nature does not have a mechanism to correct the collapse of chemo-surveillance. Instead, PSCs are forced to evolve into cancer stem cells (CSCs) by the silencing of TET-1 enzyme to escape contact inhibition that limits the extent PSCs can proliferate. The proliferation of CSCs still cannot heal the wound, which are then forced to progress to faster growing CCs by chromosomal abnormalities to activate oncogenes or to inactivate suppressor genes, eventually forcing CSCs to become full blown CCs. CSCs became known in 1997. The discovery of CSCs unraveled CSCs as the most important issue of cancer, because these are the cells to initiate cancer growth, and the cells responsible to cause the fatality of cancer. Elimination of CSCs is essential to the success of cancer therapy. The evolution of CSCs is critically linked to wound unhealing. Therefore, induction of terminal differentiation of CSCs is the only option to solve the issue of CSCs. CSCs are unresponsive to cytotoxic chemotherapy, radiotherapy or immunotherapy, because these cells are protected by drug resistance, anti-apoptosis mechanisms and devoid of program death antigen. Besides, these therapies contribute to the destruction of chemo-surveillance. CDA formulations are the best drugs to eliminate CSCs, which are the nature’s creation for the perfection of wound healing to avoid and to cure cancer. CDA formulations can also eliminate CCs by turning CCs into terminally differentiated cells unable to replicate. Therefore, destabilization of abnormal MEs is the right indication to direct cancer therapy.