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Sci Signal. 2017 Jan 10;10(461). pii: eaaf8223. doi: 10.1126/scisignal.aaf8223.

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

Author information

1
Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
2
Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3000, Australia.
3
The Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel.
4
Molecular Therapeutics and Biomarkers Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
5
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.
6
Biomedical Manufacturing Program, Commonwealth Scientific and Industrial Research Organization, Melbourne, Victoria 3169, Australia.
7
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
8
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
9
Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
10
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
11
Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 2555, Australia.
12
Department of Surgery, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
13
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
14
Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. ygal.haupt@petermac.org.
15
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
16
Department of Pathology, University of Melbourne, Victoria 3800, Australia.

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.

PMID:
28074012
DOI:
10.1126/scisignal.aaf8223
[Indexed for MEDLINE]

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