Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression.
DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3(-/-);Apc(1638N) and Mlh3(-/-);Pms2(-/-);Apc(1638N) (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1(-/-);Apc(1638N) mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression.
Chen
Peng-Chieh
PC
Department of Biological Chemistry, University of California Irvine, Irvine, California, USA.
Kuraguchi
Mari
M
Velasquez
John
J
Wang
Yuxun
Y
Yang
Kan
K
Edwards
Robert
R
Gillen
Dan
D
Edelmann
Winfried
W
Kucherlapati
Raju
R
Lipkin
Steven M
SM
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D000070956:MutL Proteins; D009154:Mutation; D009368:Neoplasm Transplantation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous
D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; C492407:Mlh3 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; C493730:Runx3 protein, mouse; C530203:Tle6 protein, human; C434948:Tle6 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D000070956:MutL Proteins; D045643:DNA Repair Enzymes