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Dysregulation of LINC00470 and METTL3 promotes chemoresistance and suppresses autophagy of chronic myelocytic leukaemia cells |
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| Authors: | Xun Lai Jia Wei Xue-zhong Gu Xiang-mei Yao Di-si Zhang Feng Li Yun-yan Sun |
| Affiliation: | 1. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China
Contribution: Conceptualization (equal), Methodology (equal), Project administration (equal), Resources (equal), Writing - original draft (equal);2. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China Contribution: Conceptualization (equal), Data curation (equal), Software (equal), Validation (equal);3. Department of Hematology, The First People’s Hospital of Yunnan Province, Kunming, China Contribution: Data curation (equal), Formal analysis (equal), Software (equal), Validation (equal);4. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), Methodology (equal);5. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China Contribution: Investigation (equal), Software (equal), Validation (equal), Writing - original draft (equal);6. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China Contribution: Formal analysis (equal), Methodology (equal), Validation (equal), Writing - original draft (equal);7. Department of Hematology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, China |
| Abstract: | Cytoplasmic lncRNAs have been found to directly interact with target mRNAs and regulate their stability. In this study, we aimed to study the molecular mechanism underlying the function of m6A as a central regulator in chemoresistance and CML proliferation. In this study, we established three mice groups (control group, ADR-R group and ADR-R + shLINC00470 group). We detected PTEN mRNA expression in the presence of LINC00470 in the mice models, as well as in the KCL22 and K562 cells. LINC00470 was significantly enriched for PTEN mRNA to exhibit a negative regulatory relationship between LINC00470 and PTEN mRNA. However, the alteration of LINC00470 had no effect on the luciferase activity of PTEN promoter, while the half-life of PTEN mRNA was affected. It was further validated that LINC00470 down-regulated PTEN expression by positively regulating the m6A modification of PTEN mRNA via RNA methyltransferase METTL3. Moreover, the relative expression of LC3II, Beclin-1, ATG7 and ATG5 was all decreased in cells treated with LINC00470, and down-regulated PTEN expression was observed in chemo-resistant cells, while the expression of PTEN was rescued by the transfection of shMETTL3 into chemo-resistant cells. Moreover, the knockdown of METTL3 also restored the normal level of PTEN m6A modification and LINC00470 expression in chemo-resistant cells. In conclusion, our results demonstrated the molecular mechanism underlying the effect of LINC00470 on CML by reducing the PTEN stability via RNA methyltransferase METTL3, thus leading to the inhibition of cell autophagy while promoting chemoresistance in CML. |
| Keywords: | AKT autophagy chemoresistance Chronic myelocytic leukaemia LINC00470 METTL3 PTEN |
