Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-1419, USA.
Oncogene. 2010 Nov 18;29(46):6160-71. doi: 10.1038/onc.2010.339. Epub 2010 Aug 23.
Overexpression of the Yes-associated protein (YAP), and TP53 family members ΔNp63 and p73, have been independently detected in subsets of head and neck squamous cell carcinomas (HNSCCs). YAP may serve as a nuclear cofactor with ΔNp63 and p73, but the functional role of YAP and their potential relationship in HNSCCs are unknown. In this study, we show 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 with decreased expression of ΔNp63 and p73. In another subset, YAP expression is decreased but detectable in the nucleus in association with lower AKT and YAP phosphorylation, and with increased ΔNp63 and p73 expression. Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP. ΔNp63 bound to the YAP promoter and suppressed its expression. 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/or ΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs.
Yes 相关蛋白 (YAP)、TP53 家族成员 ΔNp63 和 p73 的过表达已在头颈部鳞状细胞癌 (HNSCC) 的亚群中独立检测到。YAP 可能作为核辅助因子与 ΔNp63 和 p73 一起发挥作用，但 YAP 的功能作用及其在 HNSCC 中的潜在关系尚不清楚。在本研究中，我们表明在 HNSCC 系和肿瘤的亚群中，YAP 表达增加但定位于细胞质中，与 AKT 和 YAP 磷酸化增加以及 ΔNp63 和 p73 表达减少有关。在另一个亚群中，YAP 表达减少但可检测到核内，与 AKT 和 YAP 磷酸化降低以及 ΔNp63 和 p73 表达增加有关。抑制 AKT 减少丝氨酸 127 磷酸化并增强 YAP 的核易位。ΔNp63 与 YAP 启动子结合并抑制其表达。YAP-丝氨酸 127-丙氨酸磷酸受体位点突变体的转染或 ΔNp63 敲低显着增加了核 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，YAP 作为肿瘤抑制因子的功能可能通过 AKT 丝氨酸 127 磷酸化和细胞质隔离的失调，或者通过 ΔNp63 的转录抑制，在 HNSCC 的不同亚群中失调。AKT 和/或 ΔNp63 可能是增强 HNSCC 中 YAP 介导的细胞凋亡和化疗敏感性的潜在靶点。
