Identification of CCAAT Displacement Protein (CDP/cut) as a Locus-specific Repressor of Major Histocompatibility Complex Gene Expression in Human Tumor Cells

Abstract

The human MHC 1 class I genes encode the highly polymorphic HLA class I antigen heavy chains, membrane-spanning proteins that combine with the invariant ␤ 2 -microglobulin to form the HLA class I surface antigen (1). Classical MHC class I (HLA-A, -B, and -C) antigen expression is essential for processing and presentation of peptide antigens to cytotoxic CD8ϩ lymphocytes (2). In addition, recent evidence suggests that certain classical and nonclassical class I antigens play an important role in inhibition of natural killer (NK) cell function (3-6) and certain subsets of cytotoxic T-cells (7). Therefore, changes in MHC class I gene expression can have profound effects on the overall susceptibility to NK cell and cytotoxic T-cell-mediated lysis, the net effect depending on the specific MHC Class I genes involved. Down-regulation of MHC class I gene expression is observed in many human tumors and transformed cell lines, resulting in decreased susceptibility to cytotoxic T-cell-mediated lysis (8 -13). Global down-regulation of surface class I expression can arise by several mechanisms, including loss of ␤ 2 -microglobulin or peptide transporter gene expression (9, 14). More frequently, loss of MHC class I antigen expression in tumor cells occurs at a single locus. For example, selective down-regulation of HLA-B locus gene expression has been observed in many cell lines derived from patients with metastatic melanoma (15) and colon cancer (16). The specific MHC class I alleles in a particular tumor that activate cytotoxic T-cells may be different from those that inhibit NK cell function. Therefore, understanding how MHC class I antigen expression is controlled at the level of specific loci and alleles is an important goal with possible implications for the development of vaccine-based cancer therapeutics.The mechanisms that mediate locus-specific down-regulation of MHC class I gene expression are incompletely understood. Transcriptional mechanisms appear to be involved in many cases (17-19) but have not been well characterized. The promoter and 5Ј-flanking regions of most MHC class I genes contain several highly conserved, well characterized DNA sequence elements involved in maintenance of constitutive expression (20 -22). Down-regulation of MHC class I expression due to decreased binding of members of the rel family of transcription factors to the highly conserved enhancer A element has been reported in human tumor cell lines (23) and in adenovirus-12-transformed cell lines (24). Our laboratory has previously shown that another highly conserved element, the interferon-stimulated response element, functions as a locusspecific activator of HLA-A gene expression in several

Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation

“…Locus-specific down-regulation of major histocompatibility class I gene expression is frequently observed in human tumors, leading to decreased susceptibility to cytotoxic T-cell-mediated lysis. The identification of human CDP as a locus-specific repressor of HLA-B and C gene expression (Snyder et al, 2001) provided further clues that suggest that CDP may be an important player in human hepatocarcinogenesis. Further research on CDP might lead to targets for pharmacologic or gene therapeutic strategies against human hepatocellular carcinoma.…”

Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency

“…The DNA binding proteins are transcriptional repressor proteins, some of which have been identiWed such as CCAAT displacement protein (CDP), special AT-rich sequence binding protein 1 (STAB-1), and pancreatic-duodenal homobox factor-1 (PDX-1) [52,53]. It has been shown that SATB1 and CDP negatively regulate several viral and cellular genes through interaction with histone deacetylase and histone lysine methyltransferase [54][55][56][57]. CDP is a known transcriptional repressor protein that has eVects on other viruses such as human papilloma virus and murine leukemia virus [58][59][60][61].…”

Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression

“…The three loci can be expressed at different levels in different cell types (3,4). The expression of a particular locus can be extinguished in tumor cells, which might contribute to immune evasion (3,5). In contrast, some tumor cell lines express relatively high levels of HLA-C mRNAs (4), which might be protective against NK cells (6).…”