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Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth
Michael Dewaele, … , Jean-Christophe Marine, Ernesto Guccione
Michael Dewaele, … , Jean-Christophe Marine, Ernesto Guccione
Published November 23, 2015
Citation Information: J Clin Invest. 2016;126(1):68-84. https://doi.org/10.1172/JCI82534.
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Research Article Oncology

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

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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 splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient–derived xenograft (PDX) mouse models, antisense oligonucleotide–mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.

Authors

Michael Dewaele, Tommaso Tabaglio, Karen Willekens, Marco Bezzi, Shun Xie Teo, Diana H.P. 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, Robert M. Campbell, Zahid Bonday, Vinay Tergaonkar, Mark Shackleton, Christine Blattner, Jean-Christophe Marine, Ernesto Guccione

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Figure 7

The ASO-mediated MDM4 therapeutic strategy is applicable to several tumor types.

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The ASO-mediated MDM4 therapeutic strategy is applicable to several tumo...
(A) The PSI MDM4 index was calculated, similarly to what is described in Figure 2B, for BRCA, OV, and DLBCL. For each tumor type, all values were sorted and plotted. Red area indicates the tumor specimens with a PSI MDM4 of greater than 0.4. The total percentage of tumor samples in this area is indicated in the top left corner. (B) ASO-mediated exon 6 skipping reduced in vitro colony formation of various cancer types. MCF7 breast cancer, SK-N-SH neuroblastoma, and Tov21G ovarian cancer cell lines were transfected with MDM4-targeting and scrambled control ASOs, and colony formation was evaluated using low-density colony formation assays 10 days after seeding. Graphs show quantification of the colony formation assays. Data are presented as the mean percentage of area occupied for 2 biological replicates (± SD). Immunoblot analysis of MDM4 protein expression levels is shown below.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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