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

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

Journal article

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

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

Science Signaling | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2017

DOI: 10.1126/scisignal.aaf8223

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 IN..

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University of Melbourne Researchers

Gavin Wright Author

Twishi Gulati Author

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Grants

Awarded by National Health and Medical Research Council

Funding Acknowledgements

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).