title: Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth.
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.forename: Michael
authors.initials: M
authors.lastname: Dewaele
authors.forename: Tommaso
authors.initials: T
authors.lastname: Tabaglio
authors.forename: Karen
authors.initials: K
authors.lastname: Willekens
authors.forename: Marco
authors.initials: M
authors.lastname: Bezzi
authors.forename: Shun Xie
authors.initials: SX
authors.lastname: Teo
authors.forename: Diana H P
authors.initials: DH
authors.lastname: Low
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Koh
authors.forename: Florian
authors.initials: F
authors.lastname: Rambow
authors.forename: Mark
authors.initials: M
authors.lastname: Fiers
authors.forename: Aljosja
authors.initials: A
authors.lastname: Rogiers
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.forename: Muthafar
authors.initials: M
authors.lastname: Al-Haddawi
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.forename: Els
authors.initials: E
authors.lastname: Hermans
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.forename: Hualong
authors.initials: H
authors.lastname: Yan
authors.forename: Manikandan
authors.initials: M
authors.lastname: Lakshmanan
authors.forename: Ratnacaram Chandrahas
authors.initials: RC
authors.lastname: Koumar
authors.forename: Soon Thye
authors.initials: ST
authors.lastname: Lim
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Derheimer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Zahid
authors.initials: Z
authors.lastname: Bonday
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.forename: Christine
authors.initials: C
authors.lastname: Blattner
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005091:Exons; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000502:physiology; D000068103:Serine-Arginine Splicing Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors