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

Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J. Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B. Fox, Prudence Russell, Doron Ginsberg, Brendon J. Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt

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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.

Original languageEnglish
Article numbereaaf8223
JournalScience Signaling
Issue number461
StatePublished - 10 Jan 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia to Y.H. (NHMRC 1063389 and 1026990), by a grant from the Cancer Council Victoria (1085154), and by the Victorian Endowment for Science, Knowledge, and Innovation award. C.G. was supported by a Victorian Cancer Agency-Richard Pratt Fellowship (Pratt14002).

Publisher Copyright:
© 2017 The Authors.


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