title: HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability.
abstract: Expression and cellular distribution of claudin-1, a tight junction protein, is dysregulated in colon cancer and its overexpression in colon cancer cells induced dedifferentiation and increased invasion. However, the molecular mechanism(s) underlying dysregulated claudin-1 expression in colon cancer remains poorly understood. Histone deacetylase (HDAC)-dependent histone acetylation is an important mechanism of the regulation of cancer-related genes and inhibition of HDACs induces epithelial differentiation and decreased invasion. Therefore, in this study, we examined the role of HDAC-dependent epigenetic regulation of claudin-1 in colon cancer. In this study, we show that sodium butyrate and Trichostatin A (TSA), two structurally different and widely used HDAC inhibitors, inhibited claudin-1 expression in multiple colon cancer cell lines. Further studies revealed modulation of claudin-1 mRNA stability by its 3'-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. In addition, overexpression of claudin-1 abrogated the TSA-induced inhibition of invasion in colon cancer cells suggesting functional crosstalk. Analysis of mRNA expression in colon cancer patients, showed a similar pattern of increase in claudin-1 and HDAC-2 mRNA expression throughout all stages of colon cancer. Inhibition of claudin-1 expression by HDAC-2-specific small interfering RNA further supported the role of HDAC-2 in this regulation. Taken together, we report a novel post-transcriptional regulation of claudin-1 expression in colon cancer cells and further show a functional correlation between claudin-1 expression and TSA-mediated regulation of invasion. As HDAC inhibitors are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Krishnan
authors.forename: A B
authors.initials: AB
authors.lastname: Singh
authors.forename: J J
authors.initials: JJ
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Eschrich
authors.forename: T J
authors.initials: TJ
authors.lastname: Yeatman
authors.forename: R D
authors.initials: RD
authors.lastname: Beauchamp
authors.forename: P
authors.initials: P
authors.lastname: Dhawan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D002087:Butyrates / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D062445:Claudin-1; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D002087:Butyrates; C568108:CLDN1 protein, human; D062445:Claudin-1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D012333:RNA, Messenger; C012589:trichostatin A; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2