CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells.
CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells.
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DOI：
10.18632/oncotarget.24824
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发表时间：
2018-04-03
期刊：
影响因子：
--
通讯作者：
Ukimura O
中科院分区：
文献类型：
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作者：
Ito S;Ueno A;Ueda T;Nakagawa H;Taniguchi H;Kayukawa N;Fujihara-Iwata A;Hongo F;Okihara K;Ukimura O
雄激素受体（AR）是一种配体依赖性转录因子，通过控制靶基因的表达来促进前列腺癌（PC）细胞的生长。该报告表明，冠层FGF信号调节因子2 （CNPY2）控制着PC细胞中AR蛋白的水平。我们发现AR被E3泛素连接酶、肌球蛋白调节轻链相互作用蛋白（MYLIP）泛素化，然后通过泛素-蛋白酶体途径降解。CNPY2通过抑制MYLIP与E2泛素连接酶UBE2D1之间的相互作用，降低了MYLIP的泛素化活性。CNPY2上调AR靶基因如编码前列腺特异性抗原（PSA）的KLK3基因的表达，促进PC细胞的生长。CNPY2敲低对细胞生长的抑制作用通过AR过表达得以恢复。此外，在人前列腺癌患者组织样本中，CNPY2与AR/AR靶基因的表达水平呈正相关。综上所述，这些结果表明CNPY2通过mylip介导的AR泛素化抑制AR蛋白降解，从而促进了PC细胞的生长。
The androgen receptor (AR) is a ligand-dependent transcription factor that promotes prostate cancer (PC) cell growth through control of target gene expression. This report suggests that Canopy FGF signaling regulator 2 (CNPY2) controls AR protein levels in PC cells. We found that AR was ubiquitinated by an E3 ubiquitin ligase, myosin regulatory light chain interacting protein (MYLIP) and then degraded through the ubiquitin-proteasome pathway. CNPY2 decreased the ubiquitination activity of MYLIP by inhibition of interaction between MYLIP and UBE2D1, an E2 ubiquitin ligase. CNPY2 up-regulated gene expression of AR target genes such as KLK3 gene which encodes the prostate specific antigen (PSA) and promoted cell growth of PC cells. The cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression. Furthermore, positive correlation of expression levels between CNPY2 and AR/AR target genes was observed in tissue samples from human prostate cancer patients. Together, these results suggested that CNPY2 promoted cell growth of PC cells by inhibition of AR protein degradation through MYLIP-mediated AR ubiquitination.