Functional Dissection of HOXD Cluster Genes in Regulation of Neuroblastoma Cell Proliferation and Differentiation
McCarthy, Brian A.
MetadataShow full item record
AbstractRetinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3â ² to 5â ², with HOXD1 at the 3â ² end and HOXD13 the 5â ² end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3â ² end being activated generally earlier than those positioned more 5â ² within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1) or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13) on BE(2)-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.
CitationPLoS One. 2012 Aug 7; 7(8):e40728
- Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation.
- Authors: Manohar CF, Salwen HR, Furtado MR, Cohn SL
- Issue date: 1996
- HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma.
- Authors: Mao L, Ding J, Zha Y, Yang L, McCarthy BA, King W, Cui H, Ding HF
- Issue date: 2011 Jun 15
- Hox gene expression in differentiating human neuroblastoma cells.
- Authors: Manohar CF, Furtado MR, Salwen HR, Cohn SL
- Issue date: 1993 Jul
- HOXD-AS1 is a novel lncRNA encoded in HOXD cluster and a marker of neuroblastoma progression revealed via integrative analysis of noncoding transcriptome.
- Authors: Yarmishyn AA, Batagov AO, Tan JZ, Sundaram GM, Sampath P, Kuznetsov VA, Kurochkin IV
- Issue date: 2014
- Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation.
- Authors: Cuende J, Moreno S, Bolaños JP, Almeida A
- Issue date: 2008 May 22