Ricerc@Sapienza

Notch signaling is a short-range intercellular communication system regulating stemness programs in both physiologic and neoplastic contexts, either by promoting or counteracting tumorigenesis depending on the tumor type. Therefore, Notch represents one of the most promising candidates for therapeutic targeting in several cancers. Over the last two decades, many efforts have been dedicated to antagonize Notch over-activation through the development of different blocking agents that are currently being investigated in preclinical and clinical studies. However, less attention is paid to agonize Notch in cancer contexts in which its restoration would mediate tumor suppression and, even worse, to date potential Notch agonistic agents are lacking.
Aberrant Notch signaling results from genetic and/or epigenetic alterations in the Notch pathway genes or from the deregulated activity of its upstream effectors. However, the understanding of the mechanisms differentially regulating the pathway's components in different cell types remains mostly ambiguous. Accordingly, our proposal aims to unveil the molecular machinery repressing Notch signaling and its relevance in distinct cancer types. Previously, others and we unveiled mechanistic insights into Notch regulation in Notch-dependent T-ALL, demonstrating that the expression and the transcriptional activity of Notch receptors are sustained by the histone demethylase JMJD3. Accordingly, we aim to evaluate whether a similar epigenetic mechanism could regulate Notch signaling in a specular fashion in tumor contexts in which Notch is supposed to act as a tumor suppressor, such as Acute Myeloid Leukemia, Cervical Cancer and Small-cell Lung Cancer. We hypothesize that the histone methyltransferase EZH2, conversely to JMJD3, would be implicated in the repression of Notch genes' expression and anti-tumor function in the above-mentioned cancers, making the selective targeting of EZH2 as a novel "Notch-activating" anti-tumor strategy.