title: Loss of UHRF2 expression is associated with human neoplasia, promoter hypermethylation, decreased 5-hydroxymethylcytosine, and high proliferative activity.
abstract: Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) binds to 5-hydroxymethylcytosine (5hmC), a DNA base involved in tissue development, but it is unknown how their distribution compares with each other in normal and malignant human tissues. We used IHC on human tumor specimens (160 from 19 tumor types) or normal tissue to determine the expression and distribution of UHRF2, Ki-67, and 5hmC. We also examined UHRF2 expression in cord blood progenitors and compared its expression to methylation status in 6 leukemia cell lines and 15 primary human leukemias. UHRF2 is highly expressed, paralleling that of 5hmC, in most non-neoplastic, differentiated tissue with low Ki-67 defined proliferative activity. UHRF2 is expressed in common lymphoid progenitors and mature lymphocytes but not common myeloid progenitors or monocytes. In contrast, UHRF2 immunostaining in human cancer tissues revealed widespread reduction or abnormal cytoplasmic localization which correlated with a higher Ki-67 and reduced 5hmC. UHRF2 expression is reduced in some leukemia cell lines, this correlates with promoter hypermethylation, and similar UHRF2 methylation profiles are seen in primary human leukemia samples. Thus, UHRF2 and 5hmC are widely present in differentiated human tissues, and UHRF2 protein is poorly expressed or mislocalized in diverse human cancers.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Huarui
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sweta
authors.initials: S
authors.lastname: Bhoopatiraju
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Nolan P
authors.initials: NP
authors.lastname: Schmitz
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Freeman
authors.affiliation: BioNet, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Linden
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Hallstrom
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D060787:Neoplasm Grading; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; C465619:UHRF2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: 5-hydroxymethylcytosine; UHRF1; UHRF2; leukemia; ubiquitin-like with PHD and ring finger domains 2