POLYCOMB GROUP GENES: PREDICTIVE MARKERS AND THERAPEUTIC TARGETS IN SOLID TUMORS

Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. Polycomb group genes (PcGs) are epigenetic effectors, essential for cancer stem cell self-renewal and pluripotency and have been the focus of investigation in cancer research in the last years. Two main Polycomb repressive complexes (PRC1, PRC2) mediate gene silencing through histone post-translational modifications. Several solid tumors including colorectal cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma and breast cancer show an over-expression of EZH2 (PRC2 component) and BMI-1 (PRC1 component). EZH2 and BMI-1 are two main PcG genes directly involved in the aggressiveness of a tumor, predicting poor prognosis, metastasis and chemoresistance. As we will show in this dissertation, Mel-18 (PRC1 component) may function as a tumor-suppressor by competing with BMI-1, modulating tumor aggressiveness and inhibiting metastases in breast cancer. We found genetic polymorphisms of EZH2 significantly associated to colorectal cancer patiens outcome. This results could be an important tool to predict the clinical outcome. Moreover, EZH2 was identified as an attractive target and we investigated the interaction of the EZH2 inhibitor 3Deazaneplanocin A(DZNeP) with gemcitabine in pancreatic cancer and we showed the synergism that impairs cancer stem cell self-renewal and tumorigenicity. Despite the well established role of PcGs in cancer stem cell biology, few studies dissected the clinical significance of these genes. In this thesis, through functional studies, combination therapy and correlation of single nucleotide polymorphisms with the clinical outcome we explore PcGs as predictive and prognostic factors in oncology, with particular emphasis to the identification of novel important biomarkers.