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YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets.

Ehsanian R, Brown M, Lu H, Yang XP, Pattatheyil A, Yan B, Duggal P, Chuang R, Doondeea J, Feller S, Sudol M, Chen Z, Van Waes C - Oncogene (2010)

Bottom Line: Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP.Transfection of a YAP-serine-127-alanine phosphoacceptor-site mutant or ΔNp63 knockdown significantly increased nuclear YAP and cell death.AKT and/or ΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

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Model of YAP dysregulation in HNSCCThe HNSCC subset expressing high overall YAP and decreased ΔNp63, p73 −/+TP53 exhibits serine-127 phosphorylation and cytoplasmic sequestration of YAP modulated by activated AKT. HNSCC exhibiting decreased overall YAP expession overexpress ΔNp63, p73 −/+TP53, and transcriptional repression of YAP by ΔNp63. DNp63 has also been reported to interact and inhibit p73 finction (Rocco et al., 2006).
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Figure 6: Model of YAP dysregulation in HNSCCThe HNSCC subset expressing high overall YAP and decreased ΔNp63, p73 −/+TP53 exhibits serine-127 phosphorylation and cytoplasmic sequestration of YAP modulated by activated AKT. HNSCC exhibiting decreased overall YAP expession overexpress ΔNp63, p73 −/+TP53, and transcriptional repression of YAP by ΔNp63. DNp63 has also been reported to interact and inhibit p73 finction (Rocco et al., 2006).

Mentions: In summary, we identified at least two subsets of HNSCC with predominantly different mechanisms of dysregulation of YAP tumor suppressor function (Fig. 6). The mechanisms of dysregulation include AKT-dependent serine-127 phosphorylation and cytoplasmic sequestration, and a previously unreported mechanism, wherein overexpression of ΔNp63 represses YAP gene expression. Targeting YAP phosphorylation or ΔNp63 may enhance YAP nuclear expression, inhibit cell growth and migration, and enhance apoptosis and chemosensitization in HNSCC.


YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets.

Ehsanian R, Brown M, Lu H, Yang XP, Pattatheyil A, Yan B, Duggal P, Chuang R, Doondeea J, Feller S, Sudol M, Chen Z, Van Waes C - Oncogene (2010)

Model of YAP dysregulation in HNSCCThe HNSCC subset expressing high overall YAP and decreased ΔNp63, p73 −/+TP53 exhibits serine-127 phosphorylation and cytoplasmic sequestration of YAP modulated by activated AKT. HNSCC exhibiting decreased overall YAP expession overexpress ΔNp63, p73 −/+TP53, and transcriptional repression of YAP by ΔNp63. DNp63 has also been reported to interact and inhibit p73 finction (Rocco et al., 2006).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2991596&req=5

Figure 6: Model of YAP dysregulation in HNSCCThe HNSCC subset expressing high overall YAP and decreased ΔNp63, p73 −/+TP53 exhibits serine-127 phosphorylation and cytoplasmic sequestration of YAP modulated by activated AKT. HNSCC exhibiting decreased overall YAP expession overexpress ΔNp63, p73 −/+TP53, and transcriptional repression of YAP by ΔNp63. DNp63 has also been reported to interact and inhibit p73 finction (Rocco et al., 2006).
Mentions: In summary, we identified at least two subsets of HNSCC with predominantly different mechanisms of dysregulation of YAP tumor suppressor function (Fig. 6). The mechanisms of dysregulation include AKT-dependent serine-127 phosphorylation and cytoplasmic sequestration, and a previously unreported mechanism, wherein overexpression of ΔNp63 represses YAP gene expression. Targeting YAP phosphorylation or ΔNp63 may enhance YAP nuclear expression, inhibit cell growth and migration, and enhance apoptosis and chemosensitization in HNSCC.

Bottom Line: Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP.Transfection of a YAP-serine-127-alanine phosphoacceptor-site mutant or ΔNp63 knockdown significantly increased nuclear YAP and cell death.AKT and/or ΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus