Plos Genetics|中介体亚基MED19改变前列腺癌细胞中AR的占有率和基因表达，在低雄激素下驱动MAOA表达和生长
由于前列腺细胞对雄激素和雄激素受体的依赖性，雄激素剥夺疗法（ADT）是前列腺癌治疗的主流。然而，肿瘤对ADT产生耐药性，因此有必要了解其机制。一种可能的机制是AR共同调节因子的上调，尽管只有少数与疾病有关。
我们先前鉴定了中介体复合体亚基MED19作为AR共同调节因子，并报道MED19缺失抑制AR转录活性和雄激素不敏感的LNCaP-abl细胞的生长。
因此，我们认为MED19的上调可以促进AR活性，促进雄激素非依赖性生长。本文，我们研究显示雄激素依赖性LNCaP细胞中MED19的稳定过表达促进雄激素缺乏条件下的生长。为了阐明其机制，我们测定了对照组和MED19过表达LNCaP细胞中的MED19和AR转录组及顺反子。
我们还检测了全基因组H3K27乙酰化。MED19过表达选择性地改变AR占有率、H3K27乙酰化和基因表达。
在雄激素缺乏的条件下，MED19调控的基因与ELK1调控的基因相对应，ELK1是一种结合AR N末端以诱导AR靶基因表达和增殖的转录因子，MED19和AR占据的基因组位点富集了与ELK1相关的基序。引人注目的是，MED19上调单胺氧化酶A（MAOA）的表达，MAOA是一种促进前列腺癌生长的因子。MAOA的缺失降低了雄激素非依赖性生长。MED19和AR占据MAOA启动子，MED19过表达增强AR占据和H3K27乙酰化。此外，MED19过表达增加了ELK1在MAOA启动子的占有率，ELK1缺失降低了MAOA的表达和雄激素非依赖性生长。
这表明MED19与ELK1协同调节AR在MAOA的占据和H3K27的乙酰化，上调其表达并驱动前列腺癌细胞的雄激素非依赖性。这项研究对低雄激素条件下前列腺癌细胞的生长机制提供了重要的见解，并强调了MED19-MAOA轴在这一过程中的重要性。
Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.
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