Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Autor:	Gerhart SV; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Kellner WA; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Thompson C; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Pappalardi MB; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Zhang XP; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Montes de Oca R; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Penebre E; Epizyme, Inc., Cambridge, MA, USA., Duncan K; Epizyme, Inc., Cambridge, MA, USA., Boriack-Sjodin A; Epizyme, Inc., Cambridge, MA, USA., Le B; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Majer C; Epizyme, Inc., Cambridge, MA, USA., McCabe MT; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Carpenter C; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.; Rubius Therapeutics, Boston, MA, USA., Johnson N; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Kruger RG; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA., Barbash O; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA. olena.x.barbash@gsk.com.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2018 Jun 26; Vol. 8 (1), pp. 9711. Date of Electronic Publication: 2018 Jun 26.
DOI:	10.1038/s41598-018-28002-y
Abstrakt:	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.
Databáze:	MEDLINE
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