Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling.
The genetic mechanisms responsible for increased incidence of lymphoma in immunocompromised individuals have not been fully elucidated. We show that, in a line of TCR transgenic TG-B mice, an insertional mutation in one allele of the Epm2a locus and epigenetic silencing of another led to a high rate of lymphoma with early onset. Overexpressing Epm2a suppressed the growth of established tumor cells and the development of lymphoma in the TG-B mice, while specific silencing of the locus increased tumorigenesis in the immune-deficient host. Downregulation of Epm2a expression is widespread among mouse and human lymphoma cell lines. Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway. Inactivation of Epm2a resulted in increased Wnt signaling and tumorigenesis.
Wang
Yin
Y
Division of Cancer Immunology, Department of Pathology, and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Liu
Yan
Y
Wu
Cindy
C
Zhang
Huiming
H
Zheng
Xincheng
X
Zheng
Zhi
Z
Geiger
Terrence L
TL
Nuovo
Gerard J
GJ
Liu
Yang
Y
Zheng
Pan
P
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D019175:DNA Methylation; D054637:Dual-Specificity Phosphatases; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D015398:Signal Transduction; D015996:Survival Rate; D051153:Wnt Proteins / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human