Oncometabolite induced primary cilia loss in pheochromocytoma.
Oncometabolite induced primary cilia loss in pheochromocytoma.
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DOI：
10.1530/erc-18-0134
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Chapple JP
中科院分区：
文献类型：
--
作者：
O'Toole SM;Watson DS;Novoselova TV;Romano LEL;King PJ;Bradshaw TY;Thompson CL;Knight MM;Sharp TV;Barnes MR;Srirangalingam U;Drake WM;Chapple JP
初级纤毛是参与细胞信号调节的感觉细胞器。纤毛缺失在肿瘤中经常被观察到;然而，肿瘤发生的负责机制和后果仍然不清楚。我们证明，纤毛的结构和功能是破坏人类嗜铬细胞瘤-肾上腺髓质内分泌肿瘤。这是伴随着纤毛介导的信号转导通路内的转录变化，与肿瘤发生一般和嗜铬细胞瘤具体。重要的是，纤毛丧失在与假性缺氧相关的基因SDHx和VHL中发生种系突变的患者中最为显著。使用来自大鼠的嗜铬细胞瘤细胞系，我们表明，缺氧和癌代谢产物诱导的假性缺氧是纤毛损失的关键驱动因素，并确定这依赖于Aurora-A/HDAC 6纤毛再吸收途径的激活。我们还表明，纤毛缺失会导致与增殖和肿瘤发生相关的显着转录变化。我们的数据提供的证据表明，原发性纤毛功能障碍有助于嗜铬细胞瘤的发病机制的缺氧/假性缺氧机制，并牵连oncometoprotein作为纤毛调节。这是重要的，因为嗜铬细胞瘤可通过包括儿茶酚胺产生和恶性转化的机制引起死亡，而缺氧是实体瘤的一般特征。此外，假性缺氧诱导的纤毛吸收可以被抑制，这表明潜在的治疗干预。
Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas – endocrine tumors of the adrenal medulla. This is concomitant with transcriptional changes within cilia-mediated signaling pathways that are associated with tumorigenesis generally and pheochromocytomas specifically. Importantly, cilia loss was most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a pheochromocytoma cell line derived from rat, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of an Aurora-A/HDAC6 cilia resorption pathway. We also show cilia loss drives dramatic transcriptional changes associated with proliferation and tumorigenesis. Our data provide evidence for primary cilia dysfunction contributing to pathogenesis of pheochromocytoma by a hypoxic/pseudohypoxic mechanism and implicates oncometabolites as ciliary regulators. This is important as pheochromocytomas can cause mortality by mechanisms including catecholamine production and malignant transformation, while hypoxia is a general feature of solid tumors. Moreover, pseudohypoxia-induced cilia resorption can be pharmacologically inhibited, suggesting potential for therapeutic intervention.