title: HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms.
abstract: HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Küçük
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Hu
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.forename: David
authors.initials: D
authors.lastname: Klinkebiel
authors.forename: Adam
authors.initials: A
authors.lastname: Cornish
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018920:Coculture Techniques; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D007376:Interleukin-2; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases