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Loss of Retinoic Acid Receptor ß Gene Expression Is Linked to Aberrant Histone H3 Acetylation in Lung Cancer Cell Lines¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [Y-A. S., H-Y. L., J. M. K.]; Hamon Center for Therapeutic Oncology Research, The University of Texas-Southwestern Medical Center, Dallas, Texas 75390-9593 [A. V., A. G.]; Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030 [J. W.]; and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and the Department of Oncology and Medicine, McGill University, Montreal, Quebec, Canada [K. K. M., W. H. M.]

Most lung cancer cell lines do not express retinoic acid receptor (RAR)-ß in response to all-trans retinoic acid (RA) because of a defect in RARß gene transcription(RA-refractory cells). Here we investigated mechanisms of RA refractoriness in 14 lung cancer cell lines. Eleven cell lines were found to be RA refractory, and in the other three cell lines, RARß levels increased with RA treatment (RA-responsive cells). We observed RARß promoter methylation in 7 of 11 RA-refractory cell lines (64%) and in 0 of the 3 RA-responsive cell lines. Treatment with 5-aza-2'-deoxycytidine restored RA response in two of the seven cell lines with RARß promoter methylation (29%). RA treatment increased acetylation of histones H3 and H4 on chromatin of the RARß promoter in RA-responsive cells. Only histone H4 acetylation increased in RA-refractory cells, including refractory cells with and without evidence of promoter methylation. Thus, loss of histone H3 acetylation consistently correlated with RA refractoriness in lung cancer cell lines. RA refractoriness and aberrant histone acetylation were attributable to RARß promoter methylation in some cell lines but not in others, suggesting that multiple mechanisms contribute to this transcriptional defect in lung cancer cells.

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