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 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 second budget year of this grant, significant progress has been made in the proposed studies, which is described in detail in the Overall Project Summary section below. Briefly, we have 2 publications 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. For Aim 1, we have completed the experiments proposed in MYCN mouse tumor development studies. For Aim 2, we have developed a culture system for enriching and long-term propagating neuroblastoma stem cell and shown that high Hoxc9 expression is essential for their differentiation induced by RA. For Aim 3, we have identified 3 modes of epigenetic regulation of transcription by HOXC9 that involve modulation of H3K4me3 and H3K27me3 levels, thereby providing a molecular basis for the role of KDM5B and KDM6B in the control of neuroblastoma differentiation. 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, 2014
- Accession Number
- ADA613636
Entities
People
- Han-fei Ding
Organizations
- Augusta University