期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 1, 页码 68-84出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI82534
关键词
-
资金
- Australian National Health and Medical Research Council (NHMRC)
- Pfizer Australia
- Victorian Endowment for Science, Knowledge and Innovation
- NHMRC [1058897]
- Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO) [G.0646.14N]
- Interuniversitaire Attractiepolen (IUAP) [P7/03]
- Foundation Against Cancer (Stiching tegen Kanker) [STK 2014-126]
- AGA-SINGA (SINgapore Graduate Award) fellowship
- IMCB
- A*STAR Joint Council [1134c001, 11/03/FG/07/04]
- A*STAR
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据