Journal article
Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth
Michael Dewaele, Tommaso Tabaglio, Karen Willekens, Marco Bezzi, Shun Xie Teo, Diana HP Low, Cheryl M Koh, Florian Rambow, Mark Fiers, Aljosja Rogiers, Enrico Radaelli, Muthafar Al-Haddawi, Soo Yong Tan, Els Hermans, Frederic Amant, Hualong Yan, Manikandan Lakshmanan, Ratnacaram Chandrahas Koumar, Soon Thye Lim, Frederick A Derheimer Show all
JOURNAL OF CLINICAL INVESTIGATION | AMER SOC CLINICAL INVESTIGATION INC | Published : 2016
DOI: 10.1172/JCI82534
Abstract
MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple sp..
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Awarded by NHMRC
Awarded by Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO)
Awarded by Interuniversitaire Attractiepolen (IUAP)
Awarded by Foundation Against Cancer (Stiching tegen Kanker)
Awarded by A*STAR Joint Council
Funding Acknowledgements
We thank P. Kaldis, D. Messerschmidt, G. Gargiulo, and M. Serresi for their helpful discussions and for critically reading the manuscript. We thank the Biological Resource Center (BRC) Shared facilities for technical support. Mark Shackleton was supported by the Australian National Health and Medical Research Council (NHMRC), Pfizer Australia, and the Victorian Endowment for Science, Knowledge and Innovation. J.-C. Marine acknowledges support from the NHMRC (grant 1058897); the Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO, grant G.0646.14N); the Interuniversitaire Attractiepolen (IUAP, grant P7/03); and the Foundation Against Cancer (Stiching tegen Kanker, grant STK 2014-126). This work was also supported by an AGA-SINGA (SINgapore Graduate Award) fellowship to M. Bezzi and T. Tabaglio; and by the IMCB, A*STAR. E. Guccione acknowledges support from A*STAR Joint Council grants 1134c001 and 11/03/FG/07/04.