Hedrick Erik, Cheng Yating, Jin Un-Ho, Kim Kyounghyun, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
Oncotarget. 2016 Apr 19;7(16):22245-56. doi: 10.18632/oncotarget.7925.
Specificity protein (Sp) transcription factor (TF) Sp1 is overexpressed in multiple tumors and is a negative prognostic factor for patient survival. Sp1 and also Sp3 and Sp4 are highly expressed in cancer cells and in this study, we have used results of RNA interference (RNAi) to show that the three TFs individually play a role in the growth, survival and migration/invasion of breast, kidney, pancreatic, lung and colon cancer cell lines. Moreover, tumor growth in athymic nude mice bearing L3.6pL pancreatic cancer cells as xenografts were significantly decreased in cells depleted for Sp1, Sp3 and Sp4 (combined) or Sp1 alone. Ingenuity Pathway Analysis (IPA) of changes in gene expression in Panc1 pancreatic cancer cells after individual knockdown of Sp1, Sp3 and Sp4 demonstrates that these TFs regulate genes and pathways that correlated with the functional responses observed after knockdown but also some genes and pathways that inversely correlated with the functional responses. However, causal IPA analysis which integrates all pathway-dependent changes in all genes strongly predicted that Sp1-, Sp3- and Sp4-regulated genes were associated with the pro-oncogenic activity. These functional and genomic results coupled with overexpression of Sp transcription factors in tumor vs. non-tumor tissues and decreased Sp1 expression with age indicate that Sp1, Sp3 and Sp4 are non-oncogene addiction (NOA) genes and are attractive drug targets for individual and combined cancer chemotherapies.
特异性蛋白（Sp）转录因子（TF）Sp1在多种肿瘤中过表达，是患者生存的负性预后因素。Sp1以及Sp3和Sp4在癌细胞中高表达，在本研究中，我们利用RNA干扰（RNAi）的结果表明，这三种转录因子分别在乳腺癌、肾癌、胰腺癌、肺癌和结肠癌细胞系的生长、存活及迁移/侵袭中发挥作用。此外，在携带L3.6pL胰腺癌细胞异种移植的无胸腺裸鼠中，Sp1、Sp3和Sp4（联合）或单独Sp1缺失的细胞中肿瘤生长显著降低。对Panc1胰腺癌细胞中Sp1、Sp3和Sp4单独敲低后基因表达变化进行的 Ingenuity 通路分析（IPA）表明，这些转录因子调节的基因和通路与敲低后观察到的功能反应相关，但也有一些基因和通路与功能反应呈负相关。然而，整合所有基因中所有依赖通路变化的因果IPA分析强烈预测，Sp1、Sp3和Sp4调节的基因与促癌活性相关。这些功能和基因组结果，加上Sp转录因子在肿瘤组织与非肿瘤组织中的过表达以及Sp1表达随年龄降低，表明Sp1、Sp3和Sp4是非癌基因成瘾（NOA）基因，是个体和联合癌症化疗有吸引力的药物靶点。
