Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer

Gamell, C; Gulati, T; Levav-Cohen, Y; Young, RJ; Do, H; Pilling, P; Takano, E; Watkins, N; Fox, SB; Russell, P; Ginsberg, D; Monahan, BJ; Wright, G; Dobrovic, A; Haupt, S; Solomon, B; Haupt, Y

Author(s): Gamell, C; Gulati, T; Levav-Cohen, Y; Young, RJ; Do, H; Pilling, P; Takano, E; Watkins, N; Fox, SB; Russell, P; Ginsberg, D; Monahan, BJ; Wright, G; Dobrovic, A; Haupt, S; Solomon, B; Haupt, Y;
Details: Publication Year 2017-01-10,Volume 10,Issue #461,Page doi: 10.1126/scisignal.aaf8223.
Journal Title: Sci Signal
Publication Type: Journal Article
Abstract: The tumor suppressor p16INK4a, one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15INK4b, p16INK4a, and p19ARF) was decreased in E6AP-/- mouse embryo fibroblasts. E6AP induced the expression of the INK4/ARF locus at the transcriptional level by inhibiting CDC6 transcription, a gene encoding a key repressor of the locus. Luciferase assays revealed that E6AP inhibited CDC6 expression by reducing its E2F1-dependent transcription. Chromatin immunoprecipitation analysis indicated that E6AP reduced the amount of E2F1 at the CDC6 promoter. In a subset of NSCLC samples, an E6AP-low/CDC6-high/p16INK4a-low protein abundance profile correlated with low methylation of the gene encoding p16INK4a (CDKN2A) and poor patient prognosis. These findings define a previously unrecognized tumor-suppressive role for E6AP in NSCLC, reveal an alternative silencing mechanism of the INK4/ARF locus, and reveal E6AP as a potential prognostic marker in NSCLC.
Publisher: AAAS
Research Division(s): Systems Biology And Personalised Medicine
PubMed ID: 28074012
Publisher's Version: https://doi.org/10.1126/scisignal.aaf8223
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-04-06 09:27:47

Last Modified: 2017-04-10 10:13:51