title: HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma.
abstract: Differentiation status in neuroblastoma strongly affects clinical outcomes and inducing differentiation is a treatment strategy in this disease. However, the molecular mechanisms that control neuroblastoma differentiation are not well understood. Here, we show that high-level HOXC9 expression is associated with neuroblastoma differentiation and is prognostic for better survival in neuroblastoma patients. HOXC9 induces growth arrest and neuronal differentiation in neuroblastoma cells by directly targeting both cell-cycle-promoting and neuronal differentiation genes. HOXC9 expression is upregulated by retinoic acid (RA), and knockdown of HOXC9 expression confers resistance to RA-induced growth arrest and differentiation. Moreover, HOXC9 expression is epigenetically silenced in RA-resistant neuroblastoma cells, and forced HOXC9 expression is sufficient to inhibit their proliferation and tumorigenecity. These findings identified HOXC9 as a key regulator of neuroblastoma differentiation and suggested a therapeutic strategy for RA-resistant neuroblastomas through epigenetic activation of HOXC9 expression.
authors.affiliation: Cancer Center and Department of Pathology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.forename: Jane
authors.initials: J
authors.lastname: Ding
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zha
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.forename: Brian A
authors.initials: BA
authors.lastname: McCarthy
authors.forename: William
authors.initials: W
authors.lastname: King
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D016193:G1 Phase; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000401:mortality / Q000473:pathology*; D009474:Neurons / Q000166:cytology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; C522807:Hoxc9 protein, human; D014212:Tretinoin