Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer
Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer
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lncRNA ARHGAP5-AS1 的自噬降解受损促进胃癌化疗耐药
DOI：
10.1038/s41419-019-1585-2
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发表时间：
2019-05-16
影响因子：
9
通讯作者：
Jin, Hongchuan
中科院分区：
文献类型：
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作者：
Zhu, Liyuan;Zhu, Yiran;Jin, Hongchuan
由于许多遗传和表观遗传的改变，化学耐药性仍然是癌症治疗的最主要阻碍因素。长非编码 RNA (lncRNA) 是促进癌症发生和进展的新兴参与者。然而，化学抗性的调节和功能在很大程度上尚不清楚。在此，我们确定 ARHGAP5-AS1 是化疗耐药性胃癌细胞中上调的 lncRNA，其敲低可逆转化疗耐药性。同时，ARHGAP5-AS1的高表达与胃癌患者的不良预后相关。有趣的是，其丰度受到自噬的影响，SQSTM1 负责将 ARHGAP5-AS1 转运至自噬体。因此，化疗耐药细胞中自噬的抑制导致 ARHGAP5-AS1 的上调。反过来，它通过直接与 ARHGAP5 启动子相互作用激活细胞核中 ARHGAP5 的转录。有趣的是，ARHGAP5-AS1还通过招募METTL3刺激ARHGAP5 mRNA的m(6)A修饰来稳定细胞质中的ARHGAP5 mRNA。结果，ARHGAP5 上调以促进化疗耐药，并且其上调也与胃癌的不良预后相关。总之，化疗耐药癌细胞中 lncRNA ARHGAP5-AS1 的自噬降解受损促进了化疗耐药。它可以激活细胞核中ARHGAP5的转录，并通过招募METTL3刺激ARHGAP5 mRNA的m(6)A修饰，从而稳定细胞质中的ARHGAP5 mRNA。因此，靶向ARHGAP5-AS1/ARHGAP5轴可能是克服胃癌化疗耐药性的一个有前途的策略。
Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m(6)A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m(6)A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.