Abstract
Transcriptional regulation is at the heart of gene regulation, in turn decisive for all physiopathological processes. Ultimately, it is governed by sequence-specific Transcription Factors (TFs) -and cofactors- recognizing genetic elements in genomes. TFs dictate switches in cell identities, including malignant transformation of normal cells. Recent analyses from the Pan-Cancer genome project revealed that 28% of adult cancers harbour focal amplification of the oncogenic MYC TF family (MYC, MYCN and MYCL). Among other tumors, MYCN amplification is found frequently in Neuroblastomas (NB). Many questions currently regard what distinguishes MYC(N)-amplified from non-amplified tumours, including what accounts for the particularly aggressive phenotypes of the MYC-amplified subtypes. Our efforts are aimed to understand how MYC(N)-amplification drives formation of aggressive cancers whose high incidence across adult and pediatric types adds urgency and significance to the present Project. We provide preliminary findings that in childhood NB amplified/overexpressed MYCN establishes a functional axis with E2F3, specifically with the E2F3a isoform, strongly correlated to the development of malignancy. We show that high MYCN is the condition for recruitment of the KAT2A/GCN5 histone acetyltransferase to MYC/E2F3 chromatin sites in NB cells. In turn, this partnership has relevant impact on generation of NB transcriptional profiles leading to aggressive phenotypes. To understand how the E2F3-MYCN-KAT2A axis influences cancer development we will determine the structural requirements for molecular interactions and unravel their role in gene regulation. Specifically, we want to explain the molecular logic behind the E2F3 isoforms-specific regulation. Our general focus will be to define their interdependence in the genesis and progression of MYCN-amplified NB. To do this, we will exploit biochemical and structural biology strategies coupled to molecular and cellular genetics to underpin and pursue the following 3 aims: 1) To dissect and define the structural determinants that allow formation of the MYCN/E2F3a/KAT2A interactions. 2) To determine how KAT2A recruitment at MYCN/E2F3a genomic sites can affect local acetylation/succinylation of histones and/or that of E2F3a/MYCN. 3) To determine how KAT2A impacts on gene expression regulated by the E2F3a/MYCN complex and contribute to the oncogenic program. Our study will shed light on the molecular bases leading to the E2F3-MYCN-KAT2A axis, and will detail how their interaction orchestrates gene transcription to drive formation of highly malignant tumors. The findings will enable us to disclose molecular vulnerabilities to be eventually employed for the screen and set up of novel and more effective therapeutic drugs.
Dettagli del progetto
Responsabile scientifico: Giovanni Perini
Strutture Unibo coinvolte:
Dipartimento di Farmacia e Biotecnologie
Coordinatore:
Università degli Studi di MILANO(Italy)
Contributo totale Unibo: Euro (EUR) 95.000,00
Durata del progetto in mesi: 24
Data di inizio
05/10/2023
Data di fine:
28/02/2026
