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2016 ; 76
(6
): 1538-48
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Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in
KRAS Mutant Lung Adenocarcinomas
#MMPMID26833129
Bouillez A
; Rajabi H
; Pitroda S
; Jin C
; Alam M
; Kharbanda A
; Tagde A
; Wong KK
; Kufe D
Cancer Res
2016[Mar]; 76
(6
): 1538-48
PMID26833129
show ga
Dysregulation of MYC expression is a hallmark of cancer, but the development of
agents that target MYC has remained challenging. The oncogenic MUC1-C
transmembrane protein is, like MYC, aberrantly expressed in diverse human
cancers. The present studies demonstrate that MUC1-C induces MYC expression in
KRAS mutant non-small cell lung cancer (NSCLC) cells, an effect that can be
suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or
pharmacologic inhibition with GO-203. MUC1-C activated the WNT/?-catenin (CTNNB1)
pathway and promoted occupancy of MUC1-C/?-catenin/TCF4 complexes on the MYC
promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase
(EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene
transcription. We also show that targeting MUC1-C decreased the expression of key
MYC target genes essential for the growth and survival of NSCLC cells, such as
TERT and CDK4. Based on these results, we found that the combination of GO-203
and the BET bromodomain inhibitor JQ1, which targets MYC transcription,
synergistically suppressed MYC expression and cell survival in vitro as well as
tumor xenograft growth. Furthermore, MUC1 expression significantly correlated
with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken
together, these findings suggest a therapeutic approach for targeting
MYC-dependent cancers and provide the framework for the ongoing clinical studies
addressing the efficacy of MUC1-C inhibition in solid tumors.