HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF.
PLZF, the promyelocytic leukaemia zinc-finger protein, is a transcriptional repressor essential to development. In some acute leukaemias, a chromosomal translocation fusing the PLZF gene to that encoding the retinoic acid receptor RARalpha gives rise to a fusion protein, PLZF-RARalpha, thought to be responsible for constitutive repression of differentiation-associated genes in these cells. Repression by both PLZF and PLZF-RARalpha is sensitive to the histone deacetylase inhibitor TSA, and PLZF was previously shown to interact physically with HDAC1, a class I histone deacetylase. We here asked whether class II histone deacetylases, known to be generally involved in differentiation processes, participate in the repression mediated by PLZF and PLZF-RARalpha, and found that PLZF interacts with HDAC4 in both GST-pull-down and co-immunoprecipitation assays. Furthermore, HDAC4 is indeed involved in PLZF and PLZF-RARalpha-mediated repression, since an enzymatically dead mutant of HDAC4 released the repression, as did an siRNA that blocks HDAC4 expression. Taken together, our data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells.
UPR 9079 CNRS-Ligue Nationale Contre le Cancer, Institut André Lwoff, 7 rue Guy Môquet, 94800 Villejuif, France.
Anne
A
Chauchereau
Marion
M
Mathieu
Julie
J
de Saintignon
Roger
R
Ferreira
Linda L
LL
Pritchard
Zohair
Z
Mishal
Anne
A
Dejean
Annick
A
Harel-Bellan
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; C092037:ZBTB16 protein, human; C400300:HDAC4 protein, human; D006655:Histone Deacetylases