Loss of retinoic acid receptor beta gene expression is linked to aberrant histone H3 acetylation in lung cancer cell lines.
Most lung cancer cell lines do not express retinoic acid receptor (RAR)-beta in response to all-trans retinoic acid (RA) because of a defect in RARbeta 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, RARbeta levels increased with RA treatment (RA-responsive cells). We observed RARbeta 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 RARbeta promoter methylation (29%). RA treatment increased acetylation of histones H3 and H4 on chromatin of the RARbeta 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 RARbeta promoter methylation in some cell lines but not in others, suggesting that multiple mechanisms contribute to this transcriptional defect in lung cancer cells.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Young-Ah
YA
Suh
Ho-Young
HY
Lee
Arvind
A
Virmani
Jiemin
J
Wong
Koren K
KK
Mann
Wilson H
WH
Miller
Adi
A
Gazdar
Jonathan M
JM
Kurie
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006657:Histones; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin