Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner.
Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner.
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DOI：
10.1016/j.mcpro.2021.100064
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Bisson N
中科院分区：
文献类型：
--
作者：
Vélot L;Lessard F;Bérubé-Simard FA;Tav C;Neveu B;Teyssier V;Boudaoud I;Dionne U;Lavoie N;Bilodeau S;Pouliot F;Bisson N
前列腺癌（PCa）是男性中最常见的癌症，也是癌症死亡的第三大原因。前列腺癌的启动和生长是由雄激素受体（AR）驱动的。AR被雄激素如睾酮激活，并控制前列腺细胞增殖和存活。在这里，我们报告了雄激素依赖性LAPC 4细胞中使用BioID邻近标记蛋白质组学产生的AR信号网络。我们在未刺激的细胞中鉴定了31种AR相关蛋白。引人注目的是，AR信号网络增加到182和200蛋白，24小时或72小时的雄激素刺激后，分别为267个非冗余AR相关的候选人。在后一组中，我们确定了213个蛋白质，以前没有在数据库中报告。许多这些新的AR相关蛋白参与DNA代谢，RNA加工和RNA聚合酶II转录。此外，我们确定了44个转录因子，包括克鲁ppel样因子4（KLF 4），它们在雄激素刺激的细胞中相互作用。有趣的是，KLF 4抑制了KLK 3（PSA）基因的AR依赖性转录; AR和KLF 4也在全基因组范围内共定位。总之，我们的数据报告了AR的扩展的高置信度邻近网络，这将有助于进一步剖析前列腺癌细胞中雄激素信号转导的分子机制。BioID蛋白质组学鉴定了267个雄激素受体（AR）相关候选者Krüppel样因子4（KLF 4）是一种新的AR相互作用伴侣AR和KLF 4在全基因组范围内共定位于>4000个基因，包括KLK 3（PSA）KLF 4作为AR靶基因KLK 3（PSA）的阻遏物雄激素受体（AR）的邻近相互作用网络是从雄激素反应性前列腺癌细胞中获得的。共鉴定了267个候选者，大多数与配体刺激相关，包括Krüppel样因子4（KLF 4）。发现KLF 4和AR在包括PSA（KLK 3）在内的4097个基因上共定位，KLF 4作为抑制物，而不调节AR的表达。这些结果有助于进一步剖析前列腺细胞中雄激素信号转导的分子机制。
Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the third cause of cancer mortality. PCa initiation and growth are driven by the androgen receptor (AR). The AR is activated by androgens such as testosterone and controls prostatic cell proliferation and survival. Here, we report an AR signaling network generated using BioID proximity labeling proteomics in androgen-dependent LAPC4 cells. We identified 31 AR-associated proteins in nonstimulated cells. Strikingly, the AR signaling network increased to 182 and 200 proteins, upon 24 h or 72 h of androgenic stimulation, respectively, for a total of 267 nonredundant AR-associated candidates. Among the latter group, we identified 213 proteins that were not previously reported in databases. Many of these new AR-associated proteins are involved in DNA metabolism, RNA processing, and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, including the Kru¨ppel-like factor 4 (KLF4), which were found interacting in androgen-stimulated cells. Interestingly, KLF4 repressed the well-characterized AR-dependent transcription of the KLK3 (PSA) gene; AR and KLF4 also colocalized genome-wide. Taken together, our data report an expanded high-confidence proximity network for AR, which will be instrumental to further dissect the molecular mechanisms underlying androgen signaling in PCa cells. BioID proteomics identifies 267 androgen receptor (AR)-associated candidates Krüppel-like factor 4 (KLF4) is a new AR interaction partner AR and KLF4 colocalize genome-wide on >4000 genes, including KLK3 (PSA) KLF4 acts as a repressor for the AR target gene KLK3 (PSA) A proximity interaction network for the androgen receptor (AR) was obtained from androgen-responsive prostate cancer cells. A total of 267 candidates were identified, most associating following ligand stimulation, including Krüppel-like factor 4 (KLF4). KLF4 and AR were found to colocalize genome-wide on 4097 genes including PSA (KLK3), for which KLF4 acts as a repressor, without regulating the expression of AR. These results are instrumental to further dissect the molecular mechanisms underlying androgen signaling in prostate cells.
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