Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation

Yunhong Zha, Emily Ding, Liqun Yang, Ling Mao, Xiangwei Wang, Brian A. McCarthy, Shuang Huang, Hanfei Ding

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 3′ to 5′, with HOXD1 at the 3′ end and HOXD13 the 5′ 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 3′ end being activated generally earlier than those positioned more 5′ 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.

Original languageEnglish (US)
Article numbere40728
JournalPloS one
Volume7
Issue number8
DOIs
StatePublished - Aug 7 2012

Fingerprint

Dissection
Cell proliferation
Multigene Family
Tretinoin
Neuroblastoma
retinoic acid
multigene family
cell differentiation
Cell Differentiation
cell proliferation
Genes
Cell Proliferation
genes
Cells
cdc Genes
Growth
human cell lines
Transcription
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation. / Zha, Yunhong; Ding, Emily; Yang, Liqun; Mao, Ling; Wang, Xiangwei; McCarthy, Brian A.; Huang, Shuang; Ding, Hanfei.

In: PloS one, Vol. 7, No. 8, e40728, 07.08.2012.

Research output: Contribution to journalArticle

Zha, Yunhong ; Ding, Emily ; Yang, Liqun ; Mao, Ling ; Wang, Xiangwei ; McCarthy, Brian A. ; Huang, Shuang ; Ding, Hanfei. / Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation. In: PloS one. 2012 ; Vol. 7, No. 8.
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