Human T-cell leukemia virus type I-mediated repression of PDZ-LIM domain-containing protein 2 involves DNA methylation but independent of the viral oncoprotein tax.
Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Our recent studies have shown that one important mechanism of HTLV-I-Mediated tumorigenesis is through PDZ-LIM domain-containing protein 2 (PDLIM2) repression, although the involved mechanism remains unknown. Here, we further report that HTLV-I-Mediated PDLIM2 repression was a pathophysiological event and the PDLIM2 repression involved DNA methylation. Whereas DNA methyltransferases 1 and 3b but not 3a were upregulated in HTLV-I-transformed T cells, the hypomethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) restored PDLIM2 expression and induced death of these malignant cells. Notably, the PDLIM2 repression was independent of the viral regulatory protein Tax because neither short-term induction nor long-term stable expression of Tax could downregulate PDLIM2 expression. These studies provide important insights into PDLIM2 regulation, HTLV-I leukemogenicity, long latency, and cancer health disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, these studies also suggest potential therapeutic strategies for ATL.
University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Pengrong
P
Yan
Zhaoxia
Z
Qu
Chie
C
Ishikawa
Naoki
N
Mori
Gutian
G
Xiao
D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D019175:DNA Methylation; D000077209:Decitabine; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D060588:LIM Domain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology
D000964:Antimetabolites, Antineoplastic; D016356:Gene Products, tax; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C502929:PDLIM2 protein, human; C514970:tax protein, Human T-lymphotrophic virus 1; D000077209:Decitabine; D001374:Azacitidine