PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes
PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes
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PCA3 通过调节 LAP2α-核纤层蛋白 A 复合物来控制染色质组织和 p53 信号激活
DOI：
10.1038/s41417-021-00314-8
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发表时间：
2022
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;Ueda T;Yokoyama A;Fujihara A;Hongo F;Ukimura O
前列腺癌抗原3(PCA3)是一种前列腺癌特异性的长非编码RNA(LncRNA)。在这里，我们报道了lncRNAPCA3在前列腺癌进展中的作用，它是由核质层介导的。PCA3与层相关多肽(LAP)2α的C末端区域相互作用。Lap2α的C末端包括肿瘤抑制蛋白视网膜母细胞瘤结合区和层粘连蛋白结合区，是层粘连蛋白A核质库调节和稳定所必需的。PCA3通过与Lap2α的C末端结合来抑制Lap2α与层蛋白A的相互作用。PCA3基因敲除后核浆层蛋白A/C水平升高。总之，通过PCA3基因敲除，LAP2α在细胞核内的水平增加。在PCA3基因敲除细胞中，Hp1γ、组蛋白H3上Lys9的三甲基化(H3K9me3)和组蛋白H3上Lys36的三甲基化(H3K36me3)水平上调。相反，Lys4在组蛋白H3(H3K4me3)上的三甲基化被下调。我们进一步证明，在没有PCA3的情况下，P53信号通路的激活和细胞周期停滞被促进。这些发现支持一种独特的机制，即前列腺癌特异的lncRNA通过调节核质层池来控制染色质组织。这一提出的机制表明，癌症的进展可能是由核层介导的。
Prostate cancer antigen 3 (PCA3) is a prostate cancer-specific long noncoding RNA (lncRNA). Here, we report that lncRNAPCA3plays a role in prostate cancer progression that is mediated by nucleoplasmic lamins.PCA3interacts with the C-terminal region of lamina-associated polypeptide (LAP) 2α. The C-terminal region of LAP2α includes tumor suppressor protein retinoblastoma (pRb)- and lamin-binding domains, and it is necessary for the regulation and stabilization of the nucleoplasmic pool of lamin A.PCA3inhibits the interaction of LAP2α with lamin A through binding with the C-terminus of LAP2α. The level of nucleoplasmic lamin A/C is increased by knockdown ofPCA3. Together, the level of LAP2α within the nucleus is increased byPCA3knockdown. InPCA3knockdown cells, the levels of HP1γ, trimethylation of Lys9 on histone H3 (H3K9me3), and trimethylation of Lys36 on histone H3 (H3K36me3) are upregulated. In contrast, trimethylation of Lys4 on histone H3 (H3K4me3) is downregulated. We further demonstrate that activation of the p53 signaling pathway and cell cycle arrest are promoted in the absence ofPCA3. These findings support a unique mechanism in which prostate cancer-specific lncRNA controls chromatin organization via regulation of the nucleoplasmic pool of lamins. This proposed mechanism suggests that cancer progression may be mediated by nuclear lamins.