YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets.
YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets.
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DOI：
10.1038/onc.2010.339
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发表时间：
2010-11-18
期刊：
影响因子：
8
通讯作者：
Van Waes, C.
中科院分区：
文献类型：
--
作者：
Ehsanian, R.;Brown, M.;Lu, H.;Yang, X. P.;Pattatheyil, A.;Yan, B.;Duggal, P.;Chuang, R.;Doondeea, J.;Feller, S.;Sudol, M.;Chen, Z.;Van Waes, C.
Yes 相关蛋白 (YAP) 以及 TP53 家族成员 ΔNp63 和 p73 的过度表达（YAP 可能作为核辅因子）已在头颈鳞状细胞癌 (HNSCC) 亚群中独立检测到。 YAP 在 HNSCC 中的潜在关系和功能作用尚不清楚。在这里，我们揭示了在 HNSCC 系和肿瘤的子集中，YAP 表达增加，但局限于细胞质，与 AKT 和 YAP 磷酸化增加以及 ΔNp63 和 p73 表达减少相关。相反，YAP 表达降低，但在细胞核中可检测到，这与另一个子集中的 AKT 和 YAP 磷酸化降低以及 ΔNp63 和 p73 表达增加相关。抑制 AKT 会降低 Serine-127 磷酸化并增强 YAP 的核转位。 ΔNp63 抑制 YAP 表达并结合其启动子。 YAP-丝氨酸-127-丙氨酸磷酸受体位点突变体或 ΔNp63 敲低的转染显着增加了核 YAP 和细胞死亡。相反，YAP 敲低增强了细胞增殖、存活、迁移和顺铂化疗耐药性。因此，在 HNSCC 的不同亚型中，YAP 作为肿瘤抑制因子的功能可能会因 Serine-127 的 AKT 磷酸化和细胞质隔离或 ΔNp63 的转录抑制而失调。 AKT 和/或 ΔNp63 是增强 HNSCC 中 YAP 介导的细胞凋亡和化疗敏感性的潜在靶标。
Over-expression of Yes-associated protein (YAP), and TP53 family members ΔNp63 and p73 with which YAP may serve as a nuclear co-factor, have been independently detected in subsets of head and neck squamous cell carcinomas (HNSCC). Their potential relationship and functional role of YAP in HNSCC are unknown. Here we reveal that in a subset of HNSCC lines and tumors, YAP expression is increased but localized in the cytoplasm in association with increased AKT and YAP phosphorylation, and decreased expression of ΔNp63 and p73. Conversely, YAP expression is decreased but detectable in the nucleus in association with lower AKT and YAP phosphorylation, and increased ΔNp63 and p73 expression, in another subset. Inhibiting AKT decreased Serine-127 phosphorylation and enhanced nuclear translocation of YAP. ΔNp63 repressed YAP expression and bound its promoter. Transfection of a YAP-Serine-127-Alanine phosphoacceptor-site mutant or ΔNp63 knockdown significantly increased nuclear YAP and cell death. Conversely, YAP knockdown enhanced cell proliferation, survival, migration, and cisplatin chemoresistance. Thus, YAP function as a tumor suppressor may alternatively be dysregulated by AKT phosphorylation at Serine-127 and cytoplasmic sequestration, or by transcriptional repression by ΔNp63, in different subsets of HNSCC. AKT and/orΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCC.
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影响因子：
6.4
作者：
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