Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer
Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer
复制标题
DOI：
10.1073/pnas.1611839113
复制
发表时间：
2016-09-06
影响因子：
11.1
通讯作者：
Hieter, Philip
中科院分区：
文献类型：
--
作者：
Duffy, Supipi;Fam, Hok Khim;Hieter, Philip
体细胞拷贝数扩增和基因过表达是许多癌症的共同特征。为了确定基因过表达对染色体不稳定性（CIN）的作用，我们在芽殖酵母中进行了全基因组筛选，以寻找过表达时引起CIN的酵母基因，我们将其称为剂量CIN（dCIN），并鉴定了245个dCIN基因。这个基因目录揭示了已知在肿瘤中反复过表达和/或扩增的人类直系同源物。我们发现，两个基因，TDP 1，酪氨酰-DNA-磷酸二酯酶，和TAF 12，RNA聚合酶II TATA盒结合因子，导致CIN时，在人类细胞中过度表达。人Tdp 1水平升高的横纹肌肉瘤细胞系也表现出CIN，其可以通过siRNA介导的TDP 1敲低而部分挽救。dCIN基因的过表达代表了一种遗传脆弱性，可以通过靶向非关联的合成剂量致死（SDL）伴侣来利用这种遗传脆弱性选择性杀死癌细胞。在酵母中使用SDL筛选，我们确定了一组基因，当删除时，特异性地杀死具有高水平Tdp 1的细胞。一个基因是组蛋白去乙酰化酶RPD 3，已知有其抑制剂。HT 1080细胞过表达hTDP 1和横纹肌肉瘤细胞与hTdp 1水平升高更敏感组蛋白脱乙酰酶抑制剂丙戊酸（VPA）和阿司他丁A（TSA），概括了SDL在人类细胞中的相互作用，并建议VPA和TSA作为潜在的治疗药物与hTdp 1水平升高的肿瘤。本文提供的dCIN基因目录提供了一个候选列表，以识别在癌症中过表达时导致CIN的基因，然后可以通过SDL选择性靶向肿瘤。
Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.