RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma
RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma
复制标题
DOI：
10.1158/2159-8290.cd-13-0362
复制
发表时间：
2014-04-01
期刊：
影响因子：
28.2
通讯作者：
Schlisio, Susanne
中科院分区：
文献类型：
--
作者：
Chen, Zhi Xiong;Wallis, Karin;Schlisio, Susanne
在神经母细胞瘤和嗜铬细胞瘤中，遗传性KIF1B功能缺失突变与KIF1B激酶作为1p36.2肿瘤抑制因子有关。然而，其抑制肿瘤的机制尚不清楚。我们发现KIF1B亚型β (KIF1B β)与RNA解旋酶A （DHX9）相互作用，引起DHX9的核积累，随后诱导促凋亡的xiap相关因子1 (XAF1)，从而导致细胞凋亡。嗜铬细胞瘤和神经母细胞瘤起源于神经嵴祖细胞，它们在发育过程中竞争神经生长因子（NGF）等生长因子。KIF1B β是NGF竞争诱导的发育性凋亡所必需的。我们发现DHX9是由NGF剥夺刺激的细胞凋亡诱导的，并且是细胞凋亡所必需的。此外，染色体缺失1p36的神经母细胞瘤表现出KIF1B β表达缺失和DHX9核定位受损，暗示DHX9核活性缺失在神经母细胞瘤发病过程中。意义：KIF1B β具有神经母细胞瘤肿瘤抑制特性，通过激活XAF1表达，促进并需要核定位DHX9发挥其凋亡功能。KIF1B β的缺失改变了DHX9的亚细胞定位，减少了交感神经元对NGF的依赖，导致神经祖细胞的筛选减少，因此可能易导致肿瘤形成。癌症越是加大;4 (4);434 - 51。(c) 2014年AACR。
Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform beta(KIF1B beta) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF)during development. KIF1B beta is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1B beta expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. SIGNIFICANCE: KIF1B beta has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1B beta alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation. Cancer Discov; 4( 4); 434- 51. (c) 2014 AACR.