Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer
In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Journal of Pharmaceutical Analysis |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095177923000709 |
| _version_ | 1797790044779446272 |
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| author | Han Xiao Rong Zhao Wangyang Meng Yongde Liao |
| author_facet | Han Xiao Rong Zhao Wangyang Meng Yongde Liao |
| author_sort | Han Xiao |
| collection | DOAJ |
| description | In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3 (METTL3), the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC. We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression. Next, we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression. Importantly, we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing, ribosome profiling, and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout. We also constructed a model for the regulation of the translation of METTL3 and PD-L1. Finally, we found PD-L1 upregulation by STM2457 in vivo and in vitro. In conclusion, STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome. Furthermore, it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC. |
| first_indexed | 2024-03-13T01:59:10Z |
| format | Article |
| id | doaj.art-35a10b4bd69b4481a552fde285796d9f |
| institution | Directory Open Access Journal |
| issn | 2095-1779 |
| language | English |
| last_indexed | 2024-03-13T01:59:10Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmaceutical Analysis |
| spelling | doaj.art-35a10b4bd69b4481a552fde285796d9f2023-07-02T04:16:32ZengElsevierJournal of Pharmaceutical Analysis2095-17792023-06-01136625639Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancerHan Xiao0Rong Zhao1Wangyang Meng2Yongde Liao3Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author.Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, ChinaDepartment of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author.In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3 (METTL3), the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC. We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression. Next, we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression. Importantly, we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing, ribosome profiling, and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout. We also constructed a model for the regulation of the translation of METTL3 and PD-L1. Finally, we found PD-L1 upregulation by STM2457 in vivo and in vitro. In conclusion, STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome. Furthermore, it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.http://www.sciencedirect.com/science/article/pii/S2095177923000709STM2457METTL3TranslatomicsNon-small cell lung cancerPD-L1 |
| spellingShingle | Han Xiao Rong Zhao Wangyang Meng Yongde Liao Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer Journal of Pharmaceutical Analysis STM2457 METTL3 Translatomics Non-small cell lung cancer PD-L1 |
| title | Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer |
| title_full | Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer |
| title_fullStr | Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer |
| title_full_unstemmed | Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer |
| title_short | Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer |
| title_sort | effects and translatomics characteristics of a small molecule inhibitor of mettl3 against non small cell lung cancer |
| topic | STM2457 METTL3 Translatomics Non-small cell lung cancer PD-L1 |
| url | http://www.sciencedirect.com/science/article/pii/S2095177923000709 |
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