CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells
CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells
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DOI：
10.1016/j.canlet.2018.08.018
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Agami, Reuven
中科院分区：
文献类型：
--
作者：
Lopes, Rui;Korkmaz, Gozde;Agami, Reuven
乳腺癌是女性中最常见的恶性肿瘤类型，每年诊断出的新发病例约为170万例，其中大多数表达ER a（ESR 1），这是一种配体依赖性转录因子。全基因组染色质结合图谱表明，ER α可能控制数千个基因的表达，这对识别功能靶点提出了巨大挑战。最近，我们开发了一种CRISPR-Cas9功能性遗传筛选方法来鉴定ER α阳性乳腺癌细胞增殖所需的增强子。我们验证了几个候选人，包括CUTE，一个假定的ER α响应增强子位于第一内含子的CUEDC 1（CUE结构域包含蛋白质）。在这里，我们表明，CUTE控制CUEDC 1的表达，这种相互作用是必不可少的ER α介导的细胞增殖。此外，异位表达的CUEDC 1，但不是一个CUE结构域突变体，拯救缺陷的CUTE活动。最后，乳腺癌中CUEDC 1表达与ER α呈正相关。因此，CUEDC 1是ER α的功能性靶基因，并且是乳腺癌细胞增殖所必需的。
Breast cancer is the most prevalent type of malignancy in women with similar to 1.7 million new cases diagnosed annually, of which the majority express ERa (ESR1), a ligand-dependent transcription factor. Genome-wide chromatin binding maps suggest that ER alpha may control the expression of thousands of genes, posing a great challenge in identifying functional targets. Recently, we developed a CRISPR-Cas9 functional genetic screening approach to identify enhancers required for ER alpha-positive breast cancer cell proliferation. We validated several candidates, including CUTE, a putative ER alpha-responsive enhancer located in the first intron of CUEDC1 (CUE-domain containing protein). Here, we show that CUTE controls CUEDC1 expression, and that this interaction is essential for ER alpha-mediated cell proliferation. Moreover, ectopic expression of CUEDC1, but not a CUE-domain mutant, rescues the defects in CUTE activity. Finally, CUEDC1 expression correlates positively with ER alpha in breast cancer. Thus, CUEDC1 is a functional target gene of ER alpha and is required for breast cancer cell proliferation.