title: PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells.
abstract: PU.1 has previously been shown to be down-regulated in classical Hodgkin lymphoma (cHL) cells via promoter methylation. We performed bisulfite sequencing and proved that the promoter region and the -17 kb upstream regulatory element of the PU.1 gene were highly methylated. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we conditionally expressed PU.1 in 2 cHL cell lines, L428 and KM-H2. Overexpression of PU.1 induced complete growth arrest and apoptosis in both cell lines. Furthermore, in a Hodgkin lymphoma tumor xenograft model using L428 and KM-H2 cell lines, overexpression of PU.1 led to tumor regression or stable disease. Lentiviral transduction of PU.1 into primary cHL cells also induced apoptosis. DNA microarray analysis revealed that among genes related to cell cycle and apoptosis, p21 (CDKN1A) was highly up-regulated in L428 cells after PU.1 induction. Stable knockdown of p21 rescued PU.1-induced growth arrest in L428 cells, suggesting that the growth arrest and apoptosis observed are at least partially dependent on p21 up-regulation. These data strongly suggest that PU.1 is a potent tumor suppressor in cHL and that induction of PU.1 with demethylation agents and/or histone deacetylase inhibitors is worth exploring as a possible therapeutic option for patients with cHL.
authors.affiliation: Department of Hematology, Kumamoto University of Medicine, Kumamoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yuki
authors.forename: Shikiko
authors.initials: S
authors.lastname: Ueno
authors.forename: Hiro
authors.initials: H
authors.lastname: Tatetsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Iino
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.forename: Yawara
authors.initials: Y
authors.lastname: Kawano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000099232:Proto-Oncogene Protein Spi-1