title: Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
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.
authors.affiliation: Cancer Center and Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, United States of America.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zha
authors.forename: Emily
authors.initials: E
authors.lastname: Ding
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Wang
authors.forename: Brian A
authors.initials: BA
authors.lastname: McCarthy
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
mesh_terms: D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D005810:Multigene Family / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D016213:Cyclins; D018398:Homeodomain Proteins; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases