The lncRNA lincNMR regulates nucleotide metabolism via a YBX1-RRM2 axis in cancer
The lncRNA lincNMR regulates nucleotide metabolism via a YBX1-RRM2 axis in cancer
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DOI：
10.1038/s41467-020-17007-9
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发表时间：
2020-06-25
影响因子：
16.6
通讯作者：
Diederichs, Sven
中科院分区：
文献类型：
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作者：
Gandhi, Minakshi;Gross, Matthias;Diederichs, Sven
长基因间非编码RNA-核苷酸代谢调节因子（lincNMR）是在肝细胞癌中诱导产生的一种长非编码RNA（lncRNA）。它的消耗引起增殖缺陷，触发衰老并抑制肝脏中的集落形成，但也抑制乳腺癌和肺癌细胞。三标记SILAC蛋白质组学图谱揭示lincNMR耗尽细胞中关键细胞周期调节剂如关键dNTP合成酶RRM 2、TYMS和TK 1的失调，暗示lincNMR调节核苷酸代谢。LincNMR沉默降低dNTP水平，而外源性dNTP挽救由lincNMR耗尽诱导的增殖缺陷。体内RNA反义纯化（RAP-MS）将YBX 1鉴定为lincNMR的直接相互作用伴侣，lincNMR调节RRM 2、TYMS和TK 1表达并结合至其启动子区。在鸡绒毛尿囊膜（CAM）体内模型中，lincNMR耗尽的肿瘤显著更小。总之，我们发现了lincRNA，lincNMR，其通过控制核苷酸代谢的YBX 1-RRM 2-TYMS-TK 1轴调节肿瘤细胞增殖。尽管在癌症中有一些很好的功能，但大多数长非编码RNA的影响仍然未知。在这里，作者发现了lncRNA lincNMR，它在癌症中上调，并通过与YBX 1相互作用和控制核苷酸代谢来驱动细胞增殖。
Long intergenic non-coding RNA-Nucleotide Metabolism Regulator (lincNMR) is a long non-coding RNA (lncRNA) which is induced in hepatocellular carcinoma. Its depletion invokes a proliferation defect, triggers senescence and inhibits colony formation in liver, but also breast and lung cancer cells. Triple-label SILAC proteomics profiles reveal a deregulation of key cell cycle regulators in lincNMR-depleted cells like the key dNTP synthesizing enzymes RRM2, TYMS and TK1, implicating lincNMR in regulating nucleotide metabolism. LincNMR silencing decreases dNTP levels, while exogenous dNTPs rescues the proliferation defect induced by lincNMR depletion. In vivo RNA Antisense Purification (RAP-MS) identifies YBX1 as a direct interaction partner of lincNMR which regulates RRM2, TYMS and TK1 expression and binds to their promoter regions. In a Chick Chorioallantoic Membrane (CAM) in vivo model, lincNMR-depleted tumors are significantly smaller. In summary, we discover a lincRNA, lincNMR, which regulates tumor cell proliferation through a YBX1-RRM2-TYMS-TK1 axis governing nucleotide metabolism. Despite some well-characterized functions in cancer, the impact of most long non-coding RNAs remains unknown. Here, the authors discover the lncRNA lincNMR which is upregulated in cancer and drives cell proliferation by interacting with YBX1 and controlling nucleotide metabolism.