Periyasamy Manikandan, Singh Anup K, Gemma Carolina, Kranjec Christian, Farzan Raed, Leach Damien A, Navaratnam Naveenan, Pálinkás Hajnalka L, Vértessy Beata G, Fenton Tim R, Doorbar John, Fuller-Pace Frances, Meek David W, Coombes R Charles, Buluwela Laki, Ali Simak
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Nucleic Acids Res. 2017 Nov 2;45(19):11056-11069. doi: 10.1093/nar/gkx721.
Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression. This occurs through the induction of p21 (CDKN1A) and the recruitment of the repressive DREAM complex to the A3B gene promoter, such that loss of p53 through mutation, or human papilloma virus-mediated inhibition, prevents recruitment of the complex, thereby causing elevated A3B expression and cytosine deaminase activity in cancer cells. As p53 is frequently mutated in cancer, our findings provide a mechanism by which p53 loss can promote cancer mutagenesis.
癌症基因组测序表明，载脂蛋白B信使核糖核酸编辑酶催化多肽样（APOBEC）基因的胞嘧啶脱氨酶活性是多种癌症中突变的重要来源，其中APOBEC3B（A3B）的表达尤其与此类癌症突变相关。为了更好地理解导致癌症中A3B过表达的过程以及靶向A3B的可能治疗途径，我们研究了A3B基因表达的调控。在此，我们表明在不同癌症类型中A3B的表达与p53状态呈负相关，并证明这是由于p53在抑制A3B表达中起直接和关键作用。这是通过诱导p21（CDKN1A）以及将抑制性DREAM复合物募集到A3B基因启动子上而发生的，因此通过突变导致p53缺失，或人乳头瘤病毒介导的抑制作用，会阻止该复合物的募集，从而导致癌细胞中A3B表达升高和胞嘧啶脱氨酶活性增强。由于p53在癌症中经常发生突变，我们的研究结果提供了一种p53缺失可促进癌症诱变的机制。
