title: Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region.
abstract: BACKGROUND
  Several reports indicate a commonly deleted chromosomal region independent from, and distal to the TP53 locus in a variety of human tumors. In a previous study, we reported a similar finding in a rat tumor model for endometrial carcinoma (EC) and through developing a deletion map, narrowed the candidate region to 700 kb, harboring 19 genes. In the present work real-time qPCR analysis, Western blot, semi-quantitative qPCR, sequencing, promoter methylation analysis, and epigenetic gene expression restoration analyses (5-aza-2'-deoxycytidine and/or trichostatin A treatments) were used to analyze the 19 genes located within the candidate region in a panel of experimental tumors compared to control samples.
  
  
  RESULTS
  Real-time qPCR analysis suggested Hic1 (hypermethylated in cancer 1), Inpp5k (inositol polyphosphate-5-phosphatase K; a.k.a. Skip, skeletal muscle and kidney enriched inositol phosphatase) and Myo1c (myosin 1c) as the best targets for the observed deletions. No mutation in coding sequences of these genes was detected, hence the observed low expression levels suggest a haploinsufficient mode of function for these potential tumor suppressor genes. Both Inpp5k and Myo1c were down regulated at mRNA and/or protein levels, which could be rescued in gene expression restoration assays. This could not be shown for Hic1.
  
  
  CONCLUSIONS
  Innp5k and Myo1c were identified as the best targets for the deletions in the region. INPP5K and MYO1C are located adjacent to each other within the reported independent region of tumor suppressor activity located at chromosome arm 17p distal to TP53 in human tumors. There is no earlier report on the potential tumor suppressor activity of INPP5K and MYO1C, however, overlapping roles in phosphoinositide (PI) 3-kinase/Akt signaling, known to be vital for the cell growth and survival, are reported for both. Moreover, there are reports on tumor suppressor activity of other members of the gene families that INPP5K and MYO1C belong to. Functional significance of these two candidate tumor suppressor genes in cancerogenesis pathways remains to be investigated.
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. carola.oldfors@gu.se.
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg Oldfors
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. dagarciadios@gmail.com.
authors.forename: Diego Garcia
authors.initials: DG
authors.lastname: Dios
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. anna.linder@gu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Linder
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. kittichate.visuttijai@his.se.|Tumor Biology Research Group, School of Bioscience, University of Skövde, SE-54128, Skövde, Sweden. kittichate.visuttijai@his.se.
authors.forename: Kittichate
authors.initials: K
authors.lastname: Visuttijai
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. emma.samuelson@gu.se.
authors.forename: Emma
authors.initials: E
authors.lastname: Samuelson
authors.affiliation: Tumor Biology Research Group, School of Bioscience, University of Skövde, SE-54128, Skövde, Sweden. sandra.karlsson@his.se.
authors.forename: Sandra
authors.initials: S
authors.lastname: Karlsson
authors.affiliation: Institute of Mathematical Statistics, Chalmers University of Technology, SE-41296, Gothenburg, Sweden. steffan.nilsson@chalmers.se.
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Tumor Biology Research Group, School of Bioscience, University of Skövde, SE-54128, Skövde, Sweden. afrouz.behboudi@his.se.
authors.forename: Afrouz
authors.initials: A
authors.lastname: Behboudi
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D056426:Genetic Loci; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000072181:Inositol Polyphosphate 5-Phosphatases; D024461:Myosin Type I / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D024461:Myosin Type I; C460367:MYO1C protein, human; D001374:Azacitidine