Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation

Matthew L Fisher; Candace Kerr; Gautam Adhikary; Dan Grun; Wen Xu; Jeffrey W Keillor; Richard L Eckert

doi:10.1158/0008-5472.CAN-16-2032

Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation

Cancer Res. 2016 Dec 15;76(24):7265-7276. doi: 10.1158/0008-5472.CAN-16-2032. Epub 2016 Oct 25.

Authors

Matthew L Fisher¹, Candace Kerr¹, Gautam Adhikary¹, Dan Grun¹, Wen Xu¹, Jeffrey W Keillor², Richard L Eckert^{3

4

5

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Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
² Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada.
³ Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. reckert@umaryland.edu.
⁴ Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland.
⁵ Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland.
⁶ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.

Abstract

Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265-76. ©2016 AACR.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology*
Cell Line, Tumor
Cell Survival
GTP-Binding Proteins / metabolism*
Gene Expression Regulation, Neoplastic / physiology
Heterografts
Humans
Integrin alpha6beta4 / metabolism
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Phosphoproteins / metabolism
Protein Glutamine gamma Glutamyltransferase 2
Signal Transduction / physiology
Skin Neoplasms / metabolism
Skin Neoplasms / pathology*
Transcription Factors / metabolism*
Transglutaminases / metabolism*
Tumor Suppressor Proteins / metabolism*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Integrin alpha6beta4
Phosphoproteins
TP63 protein, human
Transcription Factors
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Protein Glutamine gamma Glutamyltransferase 2
Transglutaminases
GTP-Binding Proteins

Abstract

MeSH terms

Substances

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