Infectious Diseases Division, Department of Medicine, The Channing Laboratory, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2130-5. doi: 10.1073/pnas.1009933108. Epub 2011 Jan 18.
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.
尽管有疫苗可用，但人乳头瘤病毒（HPV）感染仍是导致重大癌症发病率和死亡率的原因。我们之前已经表明，HPV16 E7 与包含 E2F6 的多梳抑制复合物结合并使其减少。在这里，我们表明，组蛋白 H3 赖氨酸 27 上的抑制性三甲基标记对于多梳抑制复合物的结合是必要的，而在 HPV16 E7 表达的细胞和 HPV16 阳性的宫颈病变中，这些标记减少了。这是由 KDM6A 和 KDM6B 组蛋白 H3 赖氨酸 27 特异性去甲基酶的转录诱导引起的。HPV16 E7 介导的 KDM6B 诱导解释了宫颈癌生物标志物 p16(INK4A)的表达。此外，KDM6A 和 KDM6B 响应的同源盒基因的表达水平显著升高，表明 HPV16 E7 导致宿主上皮细胞的重编程。这些效应独立于 E7 抑制视网膜母细胞瘤肿瘤抑制蛋白的能力。最重要的是，当沉默 E7 的表达时，这些效应会逆转，这表明该途径可能具有预后和/或治疗意义。
