Dottoressa di ricerca

ciclo: XXXV

supervisore: Rocco Palermo
relatore: Rocco Palermo
co-supervisore: Isabella Screpanti

Titolo della tesi: The histone methyltransferase EZH2 represses Notch oncosuppressive program in Cervical Cancer and Acute Myeloid Leukemia

Deregulated Notch signaling, due to genetic and epigenetic alterations of Notch pathway genes, has been linked to onset, progression, and chemotherapy resistance in several solid or hematological malignancies, in which the signaling sustains or prevents tumorigenesis in a context-dependent way. Therefore, Notch modulation represents one of the most promising anticancer therapeutic approaches. Over the last two decades, different studies have focused on the molecular mechanisms underlying Notch signaling activation, and several strategies have been developed to inhibit the main steps of its pathway activation, some of which are under clinical evaluation. However, less attention is paid to unveil molecular processes suppressing Notch and new potential methods to activate the signaling in tumors in which its activation would be therapeutically relevant. Evidence indicates that epigenetic modifications at the loci of the Notch pathway components finely regulate the signaling in cancer. In particular, the regulatory regions of the Notch receptors and target genes are associated with the lack of repressive H3K27me3 marks in T cell acute lymphoblastic leukemia (T-ALL) and require the activity of the demethylase JMJD3, which pharmacological inhibition represses Notch signaling in T-ALL and colorectal cancer (CRC). Consistently, the enzymatic counterpart of JMJD3, the histone methyltransferase EZH2, counteracts the Notch oncogenic transcriptional program in T-ALL, acting as an oncosuppressor. Nonetheless, EZH2 exerts tumorigenic function in certain cancers by repressing critical tumor-suppressor genes. However, the molecular mechanisms underlying EZH2 function are not fully understood. Accordingly, we hypothesized that, specularly to JMJD3 in T-ALL and CRC, EZH2 could repress Notch in cervical cancer (CC) and acute myeloid leukemia (AML) in which the Notch pathway is silenced and its activation abrogated tumor growth, while EZH2 has been suggested as an oncogene. Consistently, we demonstrated that EZH2 inhibition significantly activated Notch signaling and reduced cell proliferation in CC and AML experimental models. Furthermore, by exploring the involvement of the EZH2-dependent Notch signaling repression in cancer maintenance, we revealed that Notch pathway inactivation partially reverted the effects of EZH2 blockage in specific subtypes of these tumors, indicating EZH2 inhibition as a promising Notch-based antitumor strategy. Moreover, by investigating the role of the EZH2-Notch axis in cancer susceptibility to current antitumor treatments, we found that in distinct CC and AML cell models, the commercially available EZH2 inhibitor, GSK126, antagonized the Doxorubicin antitumor activity, and it synergized with Cisplatin, suggesting the latter combination approach as a promising anticancer strategy in contexts in which Notch plays as an oncosuppressor.

Produzione scientifica

11573/1605213 - 2022 - MicroRNAs as Modulators of the Immune Response in T-Cell Acute Lymphoblastic Leukemia
Del Gaizo, M.; Sergio, I.; Lazzari, S.; Cialfi, S.; Pelullo, M.; Screpanti, I.; Felli, M. P. - 01g Articolo di rassegna (Review)
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 829- - issn: 1661-6596 - wos: WOS:000748219800001 (4) - scopus: 2-s2.0-85122783300 (6)

11573/1664088 - 2022 - Identification of a novel curcumin derivative influencing notch pathway and DNA damage as a potential therapeutic agent in T-ALL
Zhdanovskaya, Nadezda; Lazzari, Sara; Caprioglio, Diego; Firrincieli, Mariarosaria; Maioli, Chiara; Pace, Eleonora; Imperio, Daniela; Talora, Claudio; Bellavia, Diana; Checquolo, Saula; Mori, Mattia; Screpanti, Isabella; Minassi, Alberto; Palermo, Rocco - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:000897324700001 (3) - scopus: 2-s2.0-85143627645 (3)

11573/1602861 - 2021 - Targeting notch to maximize chemotherapeutic benefits: rationale, advanced strategies, and future perspectives
Zhdanovskaya, N.; Firrincieli, M.; Lazzari, S.; Pace, E.; Rossi, P. S.; Felli, M. P.; Talora, C.; Screpanti, I.; Palermo, R. - 01g Articolo di rassegna (Review)
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:000713815300001 (13) - scopus: 2-s2.0-85116745560 (13)

11573/1261501 - 2019 - Histone Modifications Drive Aberrant Notch3 Expression/Activity and Growth in T-ALL
Tottone, Luca; Zhdanovskaya, Nadezda; Carmona Pestaña, Álvaro; Zampieri, Michele; Simeoni, Fabrizio; Lazzari, Sara; Ruocco, Valeria; Pelullo, Maria; Caiafa, Paola; Felli, Maria Pia; Checquolo, Saula; Bellavia, Diana; Talora, Claudio; Screpanti, Isabella; Palermo, Rocco - 01a Articolo in rivista
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. 1-15 - issn: 2234-943X - wos: WOS:000463425600001 (29) - scopus: 2-s2.0-85067443438 (28)

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