HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma.
HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma.
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DOI：
10.1158/0008-5472.can-11-0051
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Ding HF
中科院分区：
文献类型：
--
作者：
Mao L;Ding J;Zha Y;Yang L;McCarthy BA;King W;Cui H;Ding HF
神经母细胞瘤的分化状态强烈影响临床结果，诱导分化是该疾病的一种治疗策略。然而，控制神经母细胞瘤分化的分子机制还不是很清楚。在这里，我们表明HOXC9的高水平表达与神经母细胞瘤的分化有关，并对神经母细胞瘤患者更好的生存具有预后意义。HOXC9通过直接靶向细胞周期促进基因和神经分化基因，诱导神经母细胞瘤细胞生长停滞和神经元分化。视黄酸(RA)上调HOXC9的表达，下调HOXC9的表达可以抵抗RA诱导的生长停滞和分化。此外，HOXC9在对RA耐药的神经母细胞瘤细胞中的表达在表观遗传上是沉默的，强制表达HOXC9足以抑制其增殖和肿瘤发生。这些发现确认HOXC9是神经母细胞瘤分化的关键调节因子，并提出了通过表观遗传激活HOXC9表达来治疗RA耐药神经母细胞瘤的策略。
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 identify HOXC9 as a key regulator of neuroblastoma differentiation and suggest a therapeutic strategy for RA-resistant neuroblastomas through epigenetic activation of HOXC9 expression.