Abstract
Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(−)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells.
Highlights
Because histone post-translational modifications influence the structure and functions of chromatin, histone lysine methylation may control many fundamental biological processes.[3]
We have proposed an adjuvant therapy that targets the epigenetics of the DNA damage response (DDR) in breast cancer (BC) cells and resulted in efficient apoptosis and the reduction of distant metastases in vivo
The wide variety of methyltransferases that are affected by this hypomethylating treatment strongly suggests that it disrupts the epigenetic machinery of BC cells and that its effects are mainly associated with a deficit in SAM in treated cells (Figure 1)
Summary
Because histone post-translational modifications influence the structure and functions of chromatin, histone lysine methylation may control many fundamental biological processes.[3]. In addition to 53BP1, BRCA1 has a decisive role in DNA DSB repair mechanisms.[8] Whereas 53BP1 inhibits end resection and facilitates non-homologous end-joining primarily during the G1 phase of the cell cycle, BRCA1 promotes DNA end resection and homologous recombination during the S/G2 phases. This competitive relationship is critical for genome integrity during cell divisions. The effects of a HMT would be reflected in the sum of its multiple effects on cellular physiology, and it is likely that the net effect of a HMT would be therapeutically favorable This nonspecificity can be viewed as advantageous because multiple defects are corrected simultaneously. It may be possible that the application of new therapies to target the epigenetic machinery of cancer cells could be used to switch resistant cancer cells to more sensible phenotypes, to promote E2F1dependent apoptosis in p53-defiant tumors, to reduce cancerinitiating cells (CICs), to prevent metastatic pathway activities and/or to sensitize tumor cells to radiotherapy.[11]
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