HOXC9-Induced Differentiation in Neuroblastoma Development
Abstract
The overall objective of this project is to test the hypothesis that HOXC9 expression levels have a causal role in determining the differentiation states of neuroblastoma tumors, with higher levels of HOXC9 promoting differentiation. At the cellular level, HOXC9 promotes the differentiation and represses the self-renewal of neuroblastoma stem cells. At the molecular level, HOXC9 activates the H3K4 demethylase KDM5B and the H3K27 demethylase KDM6B for global control of its differentiation program. During the first budget year of this grant, significant progress has been made in the proposed studies, which is described in detail in the BODY section below. Briefly, we have submitted a manuscript reporting our new findings on the molecular mechanism by which HOXC9 induces neuronal differentiation of neuroblastoma cells. We show that HOXC9 directly regulate a large number of genes involved in neuronal differentiation, upregulating neuronal genes and downregulating cell cycle and DNA repair genes. We further present evidence for an essential role of E2F6 in HOXC9 repression of cell cycle genes and induction of G1 arrest. For Aim 1, we have generated MYCN mice (a mouse neuroblastoma model) with Hoxc9 deficiency or heterozygosity and initiated the study on their effects on neuroblastoma initiation and progression. For Aim 3, we have obtained evidence for critical roles of KDM5B and KDM6B in HOXC9 control of cell cycle and neuronal genes, respectively. These findings significantly advance our molecular understanding of neuroblastoma differentiation and suggest new targets for neuroblastoma therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA598450
Entities
People
- Han-fei Ding
Organizations
- Medical College of Georgia