Polycomb group (PcG) proteins function to maintain the stable epigenetic repression of homeotic genes and other important developmental and cell cycle regulatory genes. Such maintenance establishes a form of cellular memory for its identity or state of differentiation. Accumulating evidence indicates that perturbation of this transcriptional memory may be required for tumor progression and may represent a hallmark of cancer. We have identified a novel gene encoding a human homologue of the Drosophila polycomblike protein, hPCL3. Through alternative polyadenylation and/or splicing, the gene encodes two nuclear proteins, hPCL3S and hPCL3L. Both proteins repressed transcription upon recruitment to the proximity of an HSV-tk promoter by a Gal4 DNA binding domain. Interestingly, the products of the hPCL3 gene, particularly the short form, hPCL3S, are markedly overexpressed in many types of cancers, including colon, skin, lung, rectal, cervical, uterus, and liver cancers. This increase in expression correlated with tumor progression. Both hPCL3S and hPCL3L messages were increased dramatically in most cell lines derived from various stages of melanoma and glioma tumor progression. Thus, our data link PcG deregulation to the progression of multiple cancers and may have important implications for unraveling the mechanisms of tumor progression.
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