Regulation of Differentiation of Pediatric Embryonal Tumors- Neuroblastoma

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Project Summary Specific Aim 2- To determine the molecular mechanisms by which CASZ1 regulates differentiation. Using state-of-the-art microscopy, we determined that the NB tumor suppressor CASZ1 is transiently recruited to sites of DNA damage in a poly-ADP-ribosylation dependent manner and regulates cellular sensitivity to DNA damage. The loss of CASZ1 increases cell sensitivity to DNA damage which may impact normal cellular processes during growth and differentiation. These studies were recently published Liu et al, BBRC, 2023. We used genome-wide assessments of CASZ1 DNA binding to delineate gene programs directly mediating growth arrest and differentiation. This study shows the loss of CASZ1 is linked to the oncogenic subversion of the NB Core Regulatory Circuit. CASZ1 functions as a negative regulator of transcription factors that for the oncogenic NB Core Regulatory Circuit. This study was published in Liu et al Cell Differention & Disease, 2022. Specific Aim 3. To delineate the enhancer landscape mediating NB differentiation. Studies from Project 2 aimed at identifying MYCN interactors, showed that MYCN interacted with transcription factors that form the NB Core Regulatory Circuit (CRC). This study showed HAND2 a transcription factor in the the NB -CRC recruits MYCN to invade enhancers was recently published Xu et al Cancer Research 2023. The cooperative interactions of these transcription factors in regulating oncogenesis in Neuroblastoma tumors is the first step in identifying potentially druggable transcriptional interactors that can be used to reverse the oncogenic transcriptional programs in neuroblastoma.