c-Myc deregulation induces mRNA capping enzyme dependency

TY - JOUR

T1 - c-Myc deregulation induces mRNA capping enzyme dependency

AU - Lombardi, Olivia

AU - Varshney, Dhaval

AU - Phillips, Nicola M.

AU - Cowling, Victoria H.

N1 - Research funded by Medical Research Council Senior Non-Clinical Fellowship MR/K024213/1 and Lister Prize Research Fellowship (VHC), a Wellcome Trust Centre Award 097945/Z/11/Z and Wellcome Trust Strategic Award100476/Z/12/Z and the Division of Signal Transduction Therapy, University of Dundee, funded by AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen, Merck-Serono and Pfizer.

PY - 2016/10/16

Y1 - 2016/10/16

N2 - c-Myc is a potent driver of many human cancers. Since strategies for directly targeting c-Myc protein have had limited success, upstream regulators and downstream effectors of c-Myc are being investigated as alternatives for therapeutic intervention. c-Myc regulates transcription and formation of the mRNA cap, which is important for transcript maturation and translation. However, the direct mechanism by which c-Myc upregulates mRNA capping is unclear. mRNA cap formation initiates with the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide, catalysed by mRNA capping enzyme (CE/RNGTT). Here we report that c-Myc increases the recruitment of catalytically active CE to RNA polymerase II and to its target genes. c-Myc-induced target gene expression, cell proliferation and cell transformation is highly dependent on CE, but only when c-Myc is deregulated. Cells retaining normal control of c-Myc expression are insensitive to repression of CE. c-Myc expression is also dependent on CE. Therefore, inhibiting CE provides an attractive route for selective therapeutic targeting of cancer cells which have acquired deregulated c-Myc.

AB - c-Myc is a potent driver of many human cancers. Since strategies for directly targeting c-Myc protein have had limited success, upstream regulators and downstream effectors of c-Myc are being investigated as alternatives for therapeutic intervention. c-Myc regulates transcription and formation of the mRNA cap, which is important for transcript maturation and translation. However, the direct mechanism by which c-Myc upregulates mRNA capping is unclear. mRNA cap formation initiates with the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide, catalysed by mRNA capping enzyme (CE/RNGTT). Here we report that c-Myc increases the recruitment of catalytically active CE to RNA polymerase II and to its target genes. c-Myc-induced target gene expression, cell proliferation and cell transformation is highly dependent on CE, but only when c-Myc is deregulated. Cells retaining normal control of c-Myc expression are insensitive to repression of CE. c-Myc expression is also dependent on CE. Therefore, inhibiting CE provides an attractive route for selective therapeutic targeting of cancer cells which have acquired deregulated c-Myc.

KW - c-Myc

KW - mRNA cap

KW - transcription

KW - translation

KW - cell proliferation

U2 - 10.18632/oncotarget.12701

DO - 10.18632/oncotarget.12701

M3 - Article

C2 - 27756891

SN - 1949-2553

VL - 7

SP - 82273

EP - 82288

JO - Oncotarget

JF - Oncotarget

IS - 50

ER -