Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I.
Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I.
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DOI：
10.1371/journal.pgen.1006217
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发表时间：
2016-08
期刊：
影响因子：
4.5
通讯作者：
Vincent CT
中科院分区：
文献类型：
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作者：
Dass RA;Sarshad AA;Carson BB;Feenstra JM;Kaur A;Obrdlik A;Parks MM;Prakash V;Love DK;Pietras K;Serra R;Blanchard SC;Percipalle P;Brown AM;Vincent CT
核糖体生物合成对于细胞生长和增殖是必不可少的，并且通常在癌症中升高。因此，许多癌基因和肿瘤抑制信号传导途径靶向rRNA合成。在乳腺癌中，已报道Wnt 5a的非经典Wnt信号传导拮抗肿瘤生长。在这里，我们表明，Wnt 5a快速抑制乳腺癌细胞中的rDNA基因转录，并产生染色质状态与RNA聚合酶I（Pol I）的rDNA转录减少。这些效应特别依赖于Dishevelled 1（DVL 1），它在核仁组织区（NOR）中积累并结合染色体的rDNA区域。在DVL 1结合后，Pol I转录激活因子和脱乙酰酶Sirtuin 7（SIRT 7）从rDNA基因座释放，伴随着Pol I转录机制在rDNA启动子处的解体。这些发现表明Wnt 5a通过DVL 1信号抑制rRNA转录。这为Wnt 5a如何发挥肿瘤抑制作用以及为什么破坏Wnt 5a信号传导增强体内乳腺肿瘤生长提供了一种新的机制。翻译机制的合成，包括兆道尔顿，RNA-蛋白质核糖体复合物，是细胞生长和增殖的关键驱动力。因此，核糖体的生物合成受到复杂的调控也就不足为奇了。核糖体的制造过程需要协调正常细胞和病变细胞中不同信号通路的组分。癌基因和肿瘤抑制因子都可以通过影响RNA聚合酶I介导的核糖体RNA（rRNA）转录的速率决定步骤和核糖体组装的偶联过程来影响这种协调。在这项研究中，我们调查是否分泌蛋白Wnt 5a，乳腺肿瘤生长的拮抗剂，调节乳腺癌细胞中rRNA的合成。我们发现，Wnt 5a信号的诱导干扰RNA聚合酶I机器的组装，导致抑制性rDNA染色质状态，这是不适合于活跃的rRNA基因转录。Wnt 5a信号通过刺激Dishevelled 1（DVL 1）的核仁积累来抑制rRNA合成，DVL 1是Wnt 5a信号的下游效应子，而对DVL 2或DVL 3没有这种影响。Wnt 5a诱导的DVL 1在核仁中的积累直接干扰rRNA的合成，这表明Wnt 5a在乳腺癌细胞中的肿瘤抑制作用是由DVL 1依赖性的rRNA合成抑制介导的。
Ribosome biogenesis is essential for cell growth and proliferation and is commonly elevated in cancer. Accordingly, numerous oncogene and tumor suppressor signaling pathways target rRNA synthesis. In breast cancer, non-canonical Wnt signaling by Wnt5a has been reported to antagonize tumor growth. Here, we show that Wnt5a rapidly represses rDNA gene transcription in breast cancer cells and generates a chromatin state with reduced transcription of rDNA by RNA polymerase I (Pol I). These effects were specifically dependent on Dishevelled1 (DVL1), which accumulates in nucleolar organizer regions (NORs) and binds to rDNA regions of the chromosome. Upon DVL1 binding, the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) releases from rDNA loci, concomitant with disassembly of Pol I transcription machinery at the rDNA promoter. These findings reveal that Wnt5a signals through DVL1 to suppress rRNA transcription. This provides a novel mechanism for how Wnt5a exerts tumor suppressive effects and why disruption of Wnt5a signaling enhances mammary tumor growth in vivo. Synthesis of the translation machinery, including the mega-Dalton, RNA-protein ribosome complex, serves as a key driver of cellular growth and proliferation. It is therefore unsurprising that ribosomal biogenesis is under intricate regulation. The process through which ribosomes are made entails the coordination of components from diverse signaling pathways in both normal and diseased cells. Both oncogenes and tumor suppressors can influence this orchestration by impinging upon the rate-determining steps of RNA Polymerase I-mediated transcription of ribosomal RNA (rRNA) and the coupled process of ribosome assembly. In this study we investigated whether the secreted protein Wnt5a, an antagonist of mammary tumor growth, regulates rRNA synthesis in breast cancer cells. We find that the induction of Wnt5a signaling disturbs assembly of the RNA polymerase I machinery, leading to a repressive rDNA chromatin state that is not amenable to active rRNA gene transcription. Wnt5a signaling represses rRNA synthesis by stimulating nucleolar accumulation of Dishevelled1 (DVL1), a downstream effector of Wnt5a signaling, while having no such effect on DVL2 or DVL3. Wnt5a-induced accumulation of DVL1 in the nucleolus directly interferes with the synthesis of rRNA, suggesting that a tumor suppressive effect of Wnt5a in breast cancer cells is mediated by DVL1-dependent repression of rRNA synthesis.