E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex.
OBJECTIVE
Early metastasis is a hallmark of pancreatic ductal adenocarcinoma and responsible for >90% of pancreatic cancer death. Because little is known about the biology and genetics of the metastatic process, we desired to elucidate molecular pathways mediating pancreatic cancer metastasis in vivo by an unbiased forward genetic approach.


METHODS
Highly metastatic pancreatic cancer cell populations were selected by serial in vivo passaging of parental cells with low metastatic potential and characterized by global gene expression profiling, chromatin immunoprecipitation, and in vivo metastatic assay.


RESULTS
In vivo selection of highly metastatic pancreatic cancer cells induced epithelial-mesenchymal transition (EMT), loss of E-cadherin expression, and up-regulation of mesenchymal genes such as Snail. Genetic inactivation of E-cadherin in parental cells induced EMT and increased metastasis in vivo. Silencing of E-cadherin in highly metastatic cells is mediated by a transcriptional repressor complex containing Snail and histone deacetylase 1 (HDAC1) and HDAC2. In line, mesenchymal pancreatic cancer specimens and primary cell lines from genetically engineered Kras(G12D) mice showed HDAC-dependent down-regulation of E-cadherin and high metastatic potential. Finally, transforming growth factor beta-driven E-cadherin silencing and EMT of human pancreatic cancer cells depends on HDAC activity.


CONCLUSIONS
We provide the first in vivo evidence that HDACs and Snail play an essential role in silencing E-cadherin during the metastatic process of pancreatic cancer cells. These data link the epigenetic HDAC machinery to EMT and metastasis and provide preclinical evidence that HDACs are promising targets for antimetastatic therapy.
von Burstin
Johannes
J
II. Medizinische Klinik, Technische Universität München, Munich, Germany.
Eser
Stefan
S
Paul
Mariel C
MC
Seidler
Barbara
B
Brandl
Martina
M
Messer
Marlena
M
von Werder
Alexander
A
Schmidt
Annegret
A
Mages
Jörg
J
Pagel
Philipp
P
Schnieke
Angelika
A
Schmid
Roland M
RM
Schneider
Günter
G
Saur
Dieter
D
D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C012589:trichostatin A; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases