Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers.
Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers.
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DOI：
10.1158/0008-5472.can-10-3268
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Li W;Wang L;Katoh H;Liu R;Zheng P;Liu Y
LATS 2是雅普癌蛋白的负调控因子，在前列腺癌、乳腺癌、肝癌、脑癌和血液来源的癌症中有报道其表达缺陷。然而，没有LATS 2基因的转录调控因子已被确定。LATS 2是雅普癌蛋白的负调节因子，其表达缺陷已在前列腺癌、乳腺癌、肝癌、脑癌和血癌中报道。然而，癌症中LATS 2失调的基础尚不明确。在这里，我们报告说，转录因子FOXP3的自发突变降低乳腺上皮细胞中LATS 2基因的表达。在小鼠和人类起源的正常或恶性乳腺上皮细胞中，shRNA介导的FOXP3沉默抑制LATS 2表达并增加雅普蛋白水平。LATS 2诱导需要FOXP3与LATS 2启动子中的特定序列结合，这种相互作用有助于FOXP3介导的肿瘤细胞生长抑制。为了支持这些结果，在显微切割的前列腺癌组织中，FOXP3的表达减少和体细胞突变与LATS 2表达缺陷密切相关。因此，LATS 2的缺陷性表达可归因于FOXP3缺陷，并且可能是癌症中雅普蛋白升高的主要独立决定因素。我们的研究结果确定了LATS 2在癌症中下调的新机制，并揭示了FOXP3和HIPPO通路之间的重要肿瘤抑制中继，该通路广泛涉及人类癌症。
Defective expression of LATS2, a negative regulator of YAP onco-protein, has been reported in cancer of prostate, breast, liver, brain and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in prostate, breast, liver, brain and blood cancers. However, the basis for LATS2 dysregulation in cancer is undefined. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer.