Epigenetic Editing as a Novel Therapeutics for Gynecological Cancer

Epigenetics is an important driving force to cancer. More and more genes were found epigenetically silenced in gynecological cancers. The translation of DNA methylation as biomarker for gynecological cancers may become feasible in the near future. However, the function of these potential biomarkers in cancer remains largely unknown. In addition to being a biomarker, epigenetic intervention is also leading to a new way of therapy. However, the major drawback of current epigenetic drugs is the lack of specificity. There is a need to develop a precise epigenetic targeting for the reactivation of silenced genes. Genetic engineering to manipulate genes in various diseases including cancers is not new. However, the progress has been limited due to the low efficiency of gene targeting. Since CRISPR/Cas9 system has been demonstrated as a powerful RNA-programmed genome-editing platform, the field of genome engineering has rapidly undergone a scientific revolution that promises to transform nearly every aspect of basic biological and biomedical research. The progress in genomic editing also revealed the potential in epigenomic editing. In the present study, we will elucidate the molecular mechanism of novel genes discovered by our previous methylomic studies. Since PAX1 is one of the most promising biomarkers for gynecological cancer detection, the biological function of PAX1 in cancer biology has never been investigated. We will figure out the mechanism of PAX1-mediated tumor suppressor effects, especially EGF-mediated invasion. In addition, we attempt to use PAX1 as a model of epigenetic engineering and explore the feasibility of CRISPR-mediated epigenetic editing of PAX1 as therapeutics in gynecological cancers. We will take two strategies. The first one is to replace methylated DNA fragment into an unmethylated one by CRISPR/Cas9 through homologous recombination. The second one is reprogram PAX1 histone modifications by mutated CRISPR-dCas9 system fused with epigenetic modification enzymes. Based on our solid track record in cancer epigenetics, this proposal is taking the advantages of cutting edge genome editing technology in epigenetics field. We anticipate that this combination of novel epigenetic genes and new genetic technology will successfully explore the unkown and lead to a new frontier.