RRC ID 52214
Author Goto H, Kariya R, Kudo E, Okuno Y, Ueda K, Katano H, Okada S.
Title Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma.
Journal Oncogene
Abstract Primary effusion lymphoma (PEL), which is an aggressive subgroup of B-cell lymphoma associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8, is refractory to the standard treatment, and exhibits a poor survival. Although PU.1 is downregulated in PEL, the potential role of its reduction remains to be elucidated. In this investigation, we analyzed the DNA methylation of PU.1 cis-regulatory elements in PEL and the effect of restoring PU.1 on PEL cells. The mRNA level of PU.1 was downregulated in PEL cells. The methylated promoter and enhancer regions of the PU.1 gene were detected in PEL cells. Suppression of cell growth and apoptosis were caused by the restoration of PU.1 in PEL cells. A microarray analysis revealed that interferon-stimulated genes (ISGs) including pro-apoptotic ISGs were strongly increased in BCBL-1 cells after the induction of PU.1. Reporter assays showed that PU.1 transactivated pro-apoptotic ISG promoters, such as the XAF1, OAS1 and TRAIL promoters. Mutations at the PU.1 binding sequences suppressed its transactivation. We confirmed the binding of PU.1 to the XAF1, OAS1 and TRAIL promoters in a chromatin immunoprecipitation assay. PU.1 suppressed ORF57 activation by inducing IRF7. The reinduction of PU.1 reduced formation of ascites and lymphoma cell infiltration of distant organs in PEL xenograft model mice. Collectively, PU.1 has a role in tumor suppression in PEL and its down-regulation is associated with PEL development. Restoring PU.1 with demethylation agents may be a novel therapeutic approach for PEL.
Volume 36(37)
Pages 5252-5262
Published 2017-9-14
DOI 10.1038/onc.2017.138
PII onc2017138
PMID 28481873
MeSH Animals Apoptosis / physiology Cell Line, Tumor Cell Proliferation / physiology DNA Methylation Heterografts Humans Interferon Regulatory Factor-7 / biosynthesis Interferon Regulatory Factor-7 / genetics Interferons / genetics* Interferons / pharmacology Lymphoma, Primary Effusion / genetics* Lymphoma, Primary Effusion / metabolism* Lymphoma, Primary Effusion / pathology Male Mice Mice, Inbred NOD Microarray Analysis Promoter Regions, Genetic Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism* Trans-Activators / genetics* Trans-Activators / metabolism* Transcriptional Activation Transfection
IF 7.971
Times Cited 2
Human and Animal Cells Raji