Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16
INK4A. Moreover, KDM6A-and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance. The HPV E6 and E7 proteins lack intrinsic enzymatic activities and do not act as DNA binding transcription factors; rather, they reprogram their host cells by associating with cellular signaling molecules. High-risk HPV E6 proteins target the p53 tumor suppressor for degradation, thereby thwarting p53-mediated transcriptional cytostatic and cytotoxic responses to cellular stress signals. High-risk HPV E7 oncoproteins associate with and degrade the retinoblastoma tumor suppressor (pRB), which acts as a cell cycle-specific repressive subunit of several E2F transcriptional complexes, and thereby, subvert cell cycle-dependent E2F transcriptional activities (reviewed in ref.2). The HPV E6 and E7 oncoproteins also associate with enzymes that modulate histone acetylation and thus, broadly regulate the transcriptional competence of host cell chromatin (3-8).We have previously reported that the HPV16 E7 oncoprotein associates with E2F6-containing polycomb transcriptional repressor complexes (PRCs) and that the detection of these complexes is reduced in HPV16 E7-expressing cells (9). PRCs require the histone H3 lysine 27 trimethyl (H3K27me3) mark to associate with and transcriptionally silence chromatin (reviewed in ref. 10). PRCs have been most extensively studied in Drosophila melanogaster (reviewed in ref. 11), where they establish and sustain lineage-specific epigenetic silencing of Homeobox (HOX) genes during development (12, 13). HOX proteins are master regulators of transcriptional programs that create and maintain cellular identities. Other PRC-regulated genes include the INK4A-ARF tumor suppressor locus, which encodes p16INK4A , an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and p14 ARF , an inhibitor of mdm2-mediated p53 degradation (14). Silencing through H3K27me3 involves PRC2 and PRC1. The catalytic subunit of PRC2, EZH2, is a methyl transferase that catalyzes di-and trimethylation of H3K27, whi...