Functional Dissection of HOXD Cluster Genes in Regulation of Neuroblastoma Cell Proliferation and Differentiation

Hdl Handle:
http://hdl.handle.net/10675.2/726
Title:
Functional Dissection of HOXD Cluster Genes in Regulation of Neuroblastoma Cell Proliferation and Differentiation
Authors:
Zha, Yunhong; Ding, Emily; Yang, Liqun; Mao, Ling; Wang, Xiangwei; McCarthy, Brian A.; Huang, Shuang; Ding, Han-Fei ( 0000-0001-5702-3439 )
Abstract:
Retinoic 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.
Citation:
PLoS One. 2012 Aug 7; 7(8):e40728
Issue Date:
7-Aug-2012
URI:
http://hdl.handle.net/10675.2/726
DOI:
10.1371/journal.pone.0040728
PubMed ID:
22879880
PubMed Central ID:
PMC3413684
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Georgia Cancer Center: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorZha, Yunhongen_US
dc.contributor.authorDing, Emilyen_US
dc.contributor.authorYang, Liqunen_US
dc.contributor.authorMao, Lingen_US
dc.contributor.authorWang, Xiangweien_US
dc.contributor.authorMcCarthy, Brian A.en_US
dc.contributor.authorHuang, Shuangen_US
dc.contributor.authorDing, Han-Feien_US
dc.date.accessioned2012-10-26T16:40:54Z-
dc.date.available2012-10-26T16:40:54Z-
dc.date.issued2012-08-7en_US
dc.identifier.citationPLoS One. 2012 Aug 7; 7(8):e40728en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22879880en_US
dc.identifier.doi10.1371/journal.pone.0040728en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/726-
dc.description.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.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectSignaling in Selected Disciplinesen_US
dc.subjectOncogenic Signalingen_US
dc.subjectCell Divisionen_US
dc.subjectCell Growthen_US
dc.subjectGene Expressionen_US
dc.subjectMedicineen_US
dc.subjectNeurologyen_US
dc.subjectDevelopmental and Pediatric Neurologyen_US
dc.subjectOncologyen_US
dc.subjectPediatric Oncologyen_US
dc.subjectPediatricsen_US
dc.subjectPediatric Oncologyen_US
dc.titleFunctional Dissection of HOXD Cluster Genes in Regulation of Neuroblastoma Cell Proliferation and Differentiationen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3413684en_US
dc.contributor.corporatenameGHSU Cancer Center-
dc.contributor.corporatenameDepartment of Pathology-
dc.contributor.corporatenameDepartment of Biochemistry and Molecular Biology-

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