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CpG Island promoter genes make up more than half of human genes, and a subset regulated by Polycomb-Repressive Complex 2 (PRC2
-CGI) become DNA hypermethylated and silenced in cancer. Here, we perform a systematic analysis of CGI genes across TCGA cancer types, finding that PRC2
-CGI genes are frequently prone to transcriptional upregulation as well. These upregulated PRC2
-CGI genes control important pathways such as Epithelial-Mesenchymal Transition (EMT) and TNFα-associated inflammatory response, and have greater cancer-type specificity than other CGI genes. Using publicly available chromatin datasets and genetic perturbations, we show that transcription factor binding sites (TFBSs) within distal enhancers underlie transcriptional activation of PRC2
-CGI genes, coinciding with loss of the PRC2-associated mark H3K27me3 at the linked promoter. In contrast, PRC2-free CGI genes are predominantly regulated by promoter TFBSs which are common to most cancer types. Surprisingly, a large subset of PRC2
-CGI genes that are upregulated in one cancer type are also hypermethylated/silenced in at least one other cancer type, underscoring the high degree of regulatory plasticity of these genes, likely derived from their complex regulatory control during normal development.