POLYCOMB ROLE IN CELLULAR PROLIFERATION AND TRANSFORMATION

The Polycomb Group proteins (PcGs) are present in cells nuclei as two main repressive complexes named Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). Both have been involved in several cellular functions among which the ability to promote cellular proliferation is the main PcG feature that links their activity to cancer development. Both complexes are directly involved in repressing the transcription of the Ink4aArf locus that encodes for the tumor suppressive proteins p16 and p19/Arf (p14/Arf in humans), potent inhibitors of cell growth via the positive regulation of pRb and p53 functions. Thus, since the activity of both PRC1 and PRC2 complexes is frequently enhanced in different type of human tumors, inhibition of PcG function has been proposed for many years as a potential strategy for cancer treatment. Yet, the fact that the pro-proliferative role of PcG proteins depends on the repression of the pRb and p53 pathways, of which most if not all tumors are defective, generates a scientific paradox for the effectiveness of PcG inhibition in cancer treatment. In this thesis, with the help of my colleagues, (from now on referred as we) I will present data showing how PcGs genetic depletion dramatically impairs cellular proliferation independently on the expression of the Ink4a/Arf locus or p53 and pRb activities. We also genetically demonstrate, in cell culture and in vivo, that PcGs activity is required for both the transformation and the maintenance of the transformed phenotype obtained by expression of potent oncogenes such as H-RASV12 or c-MYC in cells defective for the pathways of p53 and pRb. Finally we suggest a potential mechanism to explain the reduced proliferation/tumorigenic potential involving DNA replication control by PcG proteins. We show defects both in fork progression and fork symmetry along with increased replication origin numbers in PcGs knockout transformed cells. Collectively these data strongly support PcGs as master regulators of cellular proliferation and transformation independently on the impairment of main tumor suppressive pathways and introduce a novel general mechanism through which PcGs regulate these processes. Overall this work supports PcGs as druggable targets in tumors where oncosuppressive pathways are de-regulated and proliferation, ergo DNA replication, is enhanced.