Dottore di ricerca

ciclo: XXXIV

Titolo della tesi: Revealing the link between epigenetic modifiers and cell death pathways in lung cancer

Accumulating evidence indicate that epigenetic dysregulation is a hallmark of tumors. The histone acetyltransferases (HAT) p300/CBP are critical transcription co-activators that remodel the chromatin state, and thus genome function, in virtually all fundamental cellular processes, e.g. cell growth, DNA repair, and differentiation. It has been reported that p300 and its paralog CBP acetylate histones and other proteins which, when dysfunctional or aberrantly expressed, are implicated in various diseases including cancer. In particular, an implication of p300 and CBP is emerging in non-small cell lung cancer (NSCLC). The goal of this project was to investigate the molecular and functional roles of the p300/CBP HAT in NSCLC model cell lines, using as a tool A-485, a selective and potent catalytic inhibitor of p300/CBP. Furthermore, the use of a selective inhibitor could help to establish whether p300/CBP are promising therapeutic targets in NSCLC. First, an in silico analysis of dataset available from the NGS data from lung cancer types revealed that p300/CBP resulted mutated in about 10-15% of lung cancer. The majority of p300 and CBP genetic alterations corresponded to mutations, with a very low frequency of gene deletions or amplifications. I then developed dose-response assays that showed that A-485 specifically reduces p300/CBP-mediated histone H3 acetylation at lysine 27 and 18, while concomitantly reducing cell growth and colony formation in NSCLC cell lines differing for their p53 status. Interestingly, A-485 does not induce apoptotic cell death but activates the autophagic (increased in LC3 and reduced p62 markers) and senescence phenotypes (increased H3K9me3 and p21 level). To unravel the cross-talk between these pathways, I have developed combined protocols to inhibit key steps in independent processes: the results indicate that treatment with the late autophagic inhibitor chloroquine in combination with p300/CBP inhibition enhanced apoptotic cell death (revealed by increased PARP level), increased the sub-G1 cell population and reduced colony forming potential. Similar results were obtained by using an shRNA approach against the autophagic gene Beclin-1: silencing of Beclin-1 also reduced the cell viability and enhanced apoptosis in response to p300/CBP inhibition. Furthermore, I found that A485-induced senescence occurred through accumulation of Reactive oxygen Species (ROS), which in turn resulted in DNA damage. Inhibition of ROS production by N-acetylcysteine attenuated both A485-induced senescence and activation of the autophagic pathway, as well as counteracting A485-induced clonogenic failure. These studies demonstrate for the first time an interplay between autophagy and senescence axis, as opposed to apoptosis, in A-485-treated NSCLC cells, suggesting the involvement of a canonical autophagic pathway and the induction of senescence through ROS-mediated DNA damage. Altogether, the data obtained in this work provide new insight into the functions of p300/CBP HATs, reveal a functional interaction between autophagy and senescence, and uncover the importance of the autophagic/apoptotic response to p300/CBP inhibition in cancer.

Produzione scientifica

11573/1661959 - 2023 - Pharmacological targeting of CBP/p300 drives a redox/autophagy axis leading to senescence-induced growth arrest in non-small cell lung cancer cells
Ansari, Mohammad Salik Zeya; Stagni, Venturina; Iuzzolino, Angela; Rotili, Dante; Mai, Antonello; Del Bufalo, Donatella; Lavia, Patrizia; Degrassi, Francesca; Trisciuoglio, Daniela - 01a Articolo in rivista
rivista: CANCER GENE THERAPY (Nature Publishing Group:Brunel Road Houndmills, Basingstoke RG21 6XS United Kingdom:011 44 20 78334000, EMAIL:, INTERNET:, Fax: 011 44 20 78434640) pp. 124-136 - issn: 0929-1903 - wos: WOS:000854955000001 (7) - scopus: 2-s2.0-85138300847 (7)

11573/1658358 - 2023 - Chemically diverse S. mansoni HDAC8 inhibitors reduced viability in worm larval and adult stages
Noce, Beatrice; Di Bello, Elisabetta; Zwergel, Clemens; Fioravanti, Rossella; Valente, Sergio; Rotili, Dante; Masotti, Andrea; Ansari, Mohammad Salik Zeya; Trisciuoglio, Daniela; Chakrabarti, Alokta; Romier, Christophe; Robaa, Dina; Sippl, Wolfgang; Jung, Manfred; Häberli, Cécile; Keiser, Jennifer; Mai, Antonello - 01a Articolo in rivista
rivista: CHEMMEDCHEM (Weinheim : Wiley-VCH-Verl..) pp. - - issn: 1860-7179 - wos: WOS:000879912800001 (3) - scopus: 2-s2.0-85141693563 (4)

11573/1635728 - 2022 - Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models
Menna, M.; Fiorentino, F.; Marrocco, B.; Lucidi, A.; Tomassi, S.; Cilli, D.; Romanenghi, M.; Cassandri, M.; Pomella, S.; Pezzella, M.; Del Bufalo, D.; Zeya Ansari, M. S.; Tomasevic, N.; Mladenovic, M.; Viviano, M.; Sbardella, G.; Rota, R.; Trisciuoglio, D.; Minucci, S.; Mattevi, A.; Rotili, D.; Mai, A. - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (Editions Scientifique & Medical Elsevier:23 Rue Linois, F 75724 Paris Cedex 15 France:011 33 1 71724646, INTERNET:, Fax: 011 33 1 71724664) pp. - - issn: 0223-5234 - wos: WOS:000804176200002 (14) - scopus: 2-s2.0-85129352278 (15)

11573/1601697 - 2021 - First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53
Nowak, R. P.; Tumber, A.; Hendrix, E.; Ansari, M. S. Z.; Sabatino, M.; Antonini, L.; Andrijes, R.; Salah, E.; Mautone, N.; Pellegrini, F. R.; Simelis, K.; Kawamura, A.; Johansson, C.; Passeri, D.; Pellicciari, R.; Ciogli, A.; Del Bufalo, D.; Ragno, R.; Coleman, M. L.; Trisciuoglio, D.; Mai, A.; Oppermann, U.; Schofield, C. J.; Rotili, D. - 01a Articolo in rivista
rivista: JOURNAL OF MEDICINAL CHEMISTRY (Washington, DC: American Chemical Society) pp. 17031-17050 - issn: 0022-2623 - wos: WOS:000754727400006 (7) - scopus: 2-s2.0-85120646873 (8)

11573/1490284 - 2020 - Reverse transcriptase inhibitors promote the remodelling of nuclear architecture and induce autophagy in prostate cancer cells
Bellisai, C.; Sciamanna, I.; Rovella, P.; Giovannini, D.; Baranzini, M.; Pugliese, G. M.; Zeya Ansari, M. S.; Milite, C.; Sinibaldi-Vallebona, P.; Cirilli, R.; Sbardella, G.; Pichierri, P.; Trisciuoglio, D.; Lavia, P.; Serafino, A.; Spadafora, C. - 01a Articolo in rivista
rivista: CANCER LETTERS (Elsevier Science Ireland Limited:PO Box 85, Limerick Ireland:011 353 61 709600, 011 353 61 61944, EMAIL:, INTERNET:, Fax: 011 353 61 709114) pp. 133-145 - issn: 0304-3835 - wos: WOS:000525868400013 (13) - scopus: 2-s2.0-85081900118 (13)

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