Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Cell Death Dis. 2019 May 16;10(6):383. doi: 10.1038/s41419-019-1585-2.
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 mA 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 mA 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.
化学耐药性仍然是癌症治疗的最大障碍，这是由于许多遗传和表观遗传的改变。长链非编码 RNA（lncRNA）是促进癌症发生和发展的新兴参与者。然而，其在化学耐药性中的调节和功能在很大程度上尚不清楚。在此，我们鉴定出 ARHGAP5-AS1 是一种在化学耐药性胃癌细胞中上调的 lncRNA，其敲低可逆转化学耐药性。同时，高 ARHGAP5-AS1 表达与胃癌患者的预后不良相关。有趣的是，其丰度受自噬影响，并且 SQSTM1 负责将 ARHGAP5-AS1 运输到自噬体中。因此，在化学耐药性细胞中抑制自噬会导致 ARHGAP5-AS1 的上调。反过来，它通过直接与 ARHGAP5 启动子相互作用，在核内激活 ARHGAP5 的转录。有趣的是，ARHGAP5-AS1 还通过招募 METTL3 来稳定细胞质中的 ARHGAP5 mRNA，从而刺激 ARHGAP5 mRNA 的 mA 修饰。结果，ARHGAP5 上调以促进化学耐药性，其上调也与胃癌的预后不良相关。总之，化学耐药性癌细胞中 lncRNA ARHGAP5-AS1 的自噬降解受损促进了化学耐药性。它可以通过招募 METTL3 来激活核内 ARHGAP5 的转录并刺激 ARHGAP5 mRNA 的 mA 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学耐药性的有前途的策略。
