Abstract：
:Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Gerhart SV,Kellner WA,Thompson C,Pappalardi MB,Zhang XP,Montes de Oca R,Penebre E,Duncan K,Boriack-Sjodin A,Le B,Majer C,McCabe MT,Carpenter C,Johnson N,Kruger RG,Barbash Odoi
10.1038/s41598-018-28002-ysubject
Has Abstractpub_date
2018-06-26 00:00:00pages
9711issue
1issn
2045-2322pii
10.1038/s41598-018-28002-yjournal_volume
8pub_type
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