TY - JOUR
T1 - Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth
AU - Dewaele, Michael
AU - Tabaglio, Tommaso
AU - Willekens, Karen
AU - Bezzi, Marco
AU - teo, Shun Xie
AU - Low, Diana H. P.
AU - Koh, Cheryl M.
AU - Rambow, Florian
AU - Fiers, Mark
AU - Rogiers, Aljosja
AU - Radaelli, Enrico
AU - Al-Haddawi, Muthafar
AU - Tan, Soo Yong
AU - Hermans, Els
AU - Amant, Frederic
AU - Yan, Hualong
AU - Lakshmanan, Manikandan
AU - Koumar, Ratnacaram Chandrahas
AU - Lim, Soon Thye
AU - Derheimer, Frederick A.
AU - Campbell, Robert M.
AU - Bonday, Zahid
AU - Tergaonkar, Vinay
AU - Shackleton, Mark
AU - Blattner, Christine
AU - Marine, Jean-Christophe
AU - Guccione, Ernesto
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.1172/JCI82534
DO - https://doi.org/10.1172/JCI82534
M3 - Article
C2 - 26595814
SN - 0021-9738
VL - 126
SP - 68
EP - 84
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 1
ER -