Regulation of androgen receptor splice variant AR3 by PCGEM1.
Regulation of androgen receptor splice variant AR3 by PCGEM1.
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PCGEM1 对雄激素受体剪接变体 AR3 的调节。
DOI：
10.18632/oncotarget.7139
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Mo YY
中科院分区：
文献类型：
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作者：
Zhang Z;Zhou N;Huang J;Ho TT;Zhu Z;Qiu Z;Zhou X;Bai C;Wu F;Xu M;Mo YY
雄激素受体（AR）是前列腺发育所必需的，也是前列腺癌发病机制的主要驱动因素。因此，雄激素剥夺疗法（ADT）是晚期前列腺癌的主要治疗方法。然而，由于组成型活性 AR 剪接变体的表达而导致的去势抵抗是前列腺癌治疗的重大挑战；很少有人知道为什么 ADT 的有效性只能持续相对较短的时间。在本研究中，我们通过 RNA 沉淀和蛋白质印迹确定 PCGEM1 与剪接因子异质核核糖核蛋白 (hnRNP) A1 和 U2AF65 相互作用，表明 PCGEM1 在选择性剪接中的作用。为了支持这种可能性，PCGEM1 与 AR3 相关，AR3 是前列腺癌中主要且临床上重要的 AR 剪接变体形式。此外，雄激素剥夺（AD）会诱导 PCGEM1 并导致其在核斑点中积累。最后，我们发现 AD 诱导的 PCGEM1 调节 hnRNP A1 和 U2AF65 之间对 AR 前 mRNA 的竞争。 AD 促进 PCGEM1 与 hnRNP A1 和 U2AF65 相互作用，产生不同的后果。 PCGEM1 与 hnRNP A1 的相互作用通过外显子跳跃抑制 AR3，而其与 U2AF65 的相互作用则通过外显子化促进 AR3。我们共同证明了 AD 介导的 AR3 表达涉及 PCGEM1 和剪接因子。
The androgen receptor (AR) is required for prostate development and is also a major driver of prostate cancer pathogenesis. Thus androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, castration resistance due to expression of constitutively active AR splice variants is a significant challenge to prostate cancer therapy; little is known why effectiveness of ADT can only last for a relatively short time. In the present study, we show that PCGEM1 interacts with splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65, as determined by RNA precipitation and Western blot, suggesting a role for PCGEM1 in alternative splicing. In support of this possibility, PCGEM1 is correlated with AR3, a predominant and clinically important form of AR splice variants in prostate cancer. Moreover, androgen deprivation (AD) induces PCGEM1 and causes its accumulation in nuclear speckles. Finally, we show that the AD-induced PCGEM1 regulates the competition between hnRNP A1 and U2AF65 for AR pre-mRNA. AD promotes PCGEM1 to interact with both hnRNP A1 and U2AF65 with different consequences. While the interaction of PCGEM1 with hnRNP A1 suppresses AR3 by exon skipping, its interaction with U2AF65 promotes AR3 by exonization. Together, we demonstrate an AD-mediated AR3 expression involving PCGEM1 and splicing factors.