Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance.
Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance.
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DOI：
10.18632/genesandcancer.182
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发表时间：
2018-05-01
期刊：
影响因子：
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通讯作者：
Hollenhorst, Peter C
中科院分区：
文献类型：
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作者：
Budka, Justin A;Ferris, Mary W;Hollenhorst, Peter C
ETS家族转录因子在前列腺肿瘤发生中起主要作用，其中一些作为癌基因，另一些作为肿瘤抑制因子。ETS因子可以在一些顺式调控序列上竞争结合，但在其他序列上显示特异性结合。因此，ETS家族成员在肿瘤发生过程中的表达变化可能具有复杂的、多模态的影响。我们发现ELF1是原发性前列腺肿瘤中最常下调的ETS因子，在转移性疾病中表达进一步降低。细胞系全基因组图谱显示，ELF1具有两种不同的肿瘤抑制作用，由不同的顺式调控序列介导。首先，ELF1通过干扰ETS/AP-1顺式调控基序的致癌ETS功能，抑制细胞迁移和上皮间质转化。其次，ELF1独特地靶向并激活了促进衰老的基因。此外，ELF1的敲低增加了对多西他赛的耐药性，这表明转移性前列腺肿瘤中发现的基因组缺失可能通过RB1和ELF1的缺失来促进治疗耐药性。
ETS family transcription factors play major roles in prostate tumorigenesis with some acting as oncogenes and others as tumor suppressors. ETS factors can compete for binding at some cis-regulatory sequences, but display specific binding at others. Therefore, changes in expression of ETS family members during tumorigenesis can have complex, multimodal effects. Here we show that ELF1 was the most commonly down-regulated ETS factor in primary prostate tumors, and expression decreased further in metastatic disease. Genome-wide mapping in cell lines indicated that ELF1 has two distinct tumor suppressive roles mediated by distinct cis-regulatory sequences. First, ELF1 inhibited cell migration and epithelial-mesenchymal transition by interfering with oncogenic ETS functions at ETS/AP-1 cis-regulatory motifs. Second, ELF1 uniquely targeted and activated genes that promote senescence. Furthermore, knockdown of ELF1 increased docetaxel resistance, indicating that the genomic deletions found in metastatic prostate tumors may promote therapeutic resistance through loss of both RB1 and ELF1.