Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation.
Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation.
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DOI：
10.1016/j.taap.2008.10.013
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发表时间：
2009-02-15
影响因子：
3.8
通讯作者：
Futscher BW
中科院分区：
文献类型：
--
作者：
Jensen TJ;Wozniak RJ;Eblin KE;Wnek SM;Gandolfi AJ;Futscher BW
砷是一种人类致癌物质，与肺癌、皮肤癌和膀胱癌有关。许多潜在的机制已被认为在砷诱导的恶性肿瘤的过程中发挥作用，包括信号通路的干扰和异常的表观遗传调控。我们启动了研究，以检查非经典WNT信号通路成员WNT 5A在UROtsa细胞和亚砷酸盐[URO-ASSC]和单甲基亚砷酸[URO-MSC]恶性转化变体中的作用。我们目前的数据表明，WNT 5A是转录激活砷诱导的恶性转化过程中。这种WNT 5A转录激活与WNT 5A启动子区域中允许性组蛋白修饰的富集和抑制性修饰的减少相关。去除砷后，WNT 5A表达的表观遗传激活及其启动子的乙酰化仍然存在，这与这些细胞中锚定独立生长表型的维持一致。此外，用表观遗传修饰药物治疗支持这些表观遗传标记在控制基因表达中的功能作用。使用慢病毒shRNA减少WNT 5A大大减弱了这些细胞以锚定独立方式生长的能力。将我们的模型扩展到人膀胱癌细胞系中表明，所检查的每种细胞系也表达WNT 5A。总之，这些数据表明，表观遗传重塑的WNT 5A启动子与其转录激活，这种上调可能参与砷诱导的恶性转化。
Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggests that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modifications and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicate that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation.
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