Oct-1 DNA binding activity unresponsive to retinoblastoma protein expression prevents MHC class II induction in a non-small cell lung carcinoma cell line.
Numerous human tumor lines fail to induce major histocompatibility (MHC) class II expression following interferon-gamma (IFN-gamma) treatment, a response that is considered to be a normal function for almost all human parenchymal and connective tissue cell-types. The effect of MHC class II non-inducibility on solid tumor growth is controversial, but an extensive body of literature indicates that tumor cell MHC class II expression can lead to an antitumor response or tumor tolerance, depending on a number of variables. Thus, understanding the molecular basis for MHC class II induction failures in solid tumor cells will likely lead to ideas for manipulating the antitumor immune response. To date, a handful of tumor associated molecular anomalies have accounted for all the known failures of MHC class II inducibility. In particular, lack of the retinoblastoma tumor suppressor protein (Rb) has been shown in both human and mouse cells to be strongly associated with failure to induce MHC class II. The basis for this relationship is traceable to, among other things, high level Oct-1 DNA binding activity in Rb-defective cells, which represses the prototypical human MHC class II gene, HLA-DRA. Ordinarily, re-establishment of Rb expression leads to elimination of, or substantially reduced Oct-1 DNA binding activity and to rescue of HLA-DRA inducibility. However, in the case of one non-small cell lung carcinoma line (NSCLC), Rb re-expression failed to rescue HLA-DRA inducibility despite successful re-establishment of Rb-function. We now report that this failure is traceable to the failure of Rb to rescue normal Oct-1 function. Furthermore, histone deacetylase inhibitor treatment allows a bypass of the Rb requirement and facilitates the MHC class II induction in this NSCLC line.
Osborne
Aaron R
AR
Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, MDC Box 7, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA.
Zhang
Hongquan
H
Blanck
George
G
D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics; D059805:HLA-DR alpha-Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D050811:Octamer Transcription Factor-1; D016160:Retinoblastoma Protein