Abstract
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 RARα gives rise to a fusion protein, PLZF–RARα, thought to be responsible for constitutive repression of differentiation-associated genes in these cells. Repression by both PLZF and PLZF–RARα 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–RARα, 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–RARα-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.
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Acknowledgements
We thank XJ Wang for providing HDAC4 expression vectors, S Khochbin for HDAC5 and 6 expression vectors, W-M Yang for HDAC2 and 3 expression vectors, Z Wu for xp-HD4-(1–208) expression vector and P Chambon for RARE-TK-CAT and anti-RARα antibodies. This work was supported by grants from ARC and the European 5th FP (grant QLG1-1999-00866). MM was supported by the CNRS, RF by the Comité du Val d'Oise de la Ligue contre le Cancer.
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Chauchereau, A., Mathieu, M., de Saintignon, J. et al. HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF. Oncogene 23, 8777–8784 (2004). https://doi.org/10.1038/sj.onc.1208128
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DOI: https://doi.org/10.1038/sj.onc.1208128
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