10.1158/1541-7786.MCR-16-0083 http://scihub22266oqcxt.onion/10.1158/1541-7786.MCR-16-0083 C5107158!5107158
!27624777
free free free
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Mol+Cancer+Res
2016 ; 14
(11
): 1124-1135
Nephropedia Template TP gab.com Text Twit Text FOAVip Twit Text # English Wikipedia
Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates
TGF?1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a
and miR-4787-5p
#MMPMID27624777
Mody HR
; Hung SW
; AlSaggar M
; Griffin J
; Govindarajan R
Mol Cancer Res
2016[Nov]; 14
(11
): 1124-1135
PMID27624777
show ga
The identification of epigenetic reversal agents for use in combination
chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an
unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2
(EZH2) are emerging as potential histone methylation reversal agents for the
treatment of various solid tumors and leukemia; however, the surprisingly small
set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms
contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep),
an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone
lysine-N-methyltransferase, significantly reprograms noncoding microRNA (miRNA)
expression and dampens TGF?1-induced epithelial-to-mesenchymal (EMT) signals in
pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as
PDAC-downregulated miRNAs that were reactivated by DZNep to directly target TGF?1
for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p
reduced TGF?1 synthesis and secretion in PDAC cells and partially phenocopied
DZNep's EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRNAs
counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo
and metastases in an orthotopic mouse pancreatic tumor model. Taken together,
these findings suggest the epigenetic reprogramming of miRNAs by synthetic
histone methylation reversal agents as a viable approach to attenuate
TGF?1-induced EMT features in human PDAC and uncover putative miRNA targets
involved in the process. IMPLICATIONS: The findings support the potential for
synthetic histone methylation reversal agents to be included in future
epigenetic-chemotherapeutic combination therapies for pancreatic cancer. Mol
Cancer Res; 14(11); 1124-35. ©2016 AACR.
Please enable JavaScript to view the comments powered by Disqus. |Adenosine/administration & dosage/*analogs & derivatives/pharmacology
[MESH] |Animals
[MESH] |Antineoplastic Agents/*administration & dosage/pharmacology
[MESH] |Carcinoma, Pancreatic Ductal/*drug therapy/genetics/metabolism/pathology
[MESH] |Cell Line, Tumor
[MESH] |Cell Movement/drug effects
[MESH] |Cell Proliferation/drug effects
[MESH] |Down-Regulation
[MESH] |Epithelial-Mesenchymal Transition/drug effects
[MESH] |Gene Expression Regulation, Neoplastic/drug effects
[MESH] |Histones/metabolism
[MESH] |Humans
[MESH] |Methyltransferases/*antagonists & inhibitors/metabolism
[MESH] |Mice
[MESH] |MicroRNAs/*genetics
[MESH] |Pancreatic Neoplasms/*drug therapy/genetics/metabolism/pathology
[MESH] |Transforming Growth Factor beta1/*metabolism
[MESH] DeepDyve Pubget Overpricing