m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia
Abstract Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL....
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202304895 |
| _version_ | 1797401805692338176 |
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| author | Zijuan Wu Xiaoling Zuo Wei Zhang Yongle Li Renfu Gui Jiayan Leng Haorui Shen Bihui Pan Lei Fan Jianyong Li Hui Jin |
| author_facet | Zijuan Wu Xiaoling Zuo Wei Zhang Yongle Li Renfu Gui Jiayan Leng Haorui Shen Bihui Pan Lei Fan Jianyong Li Hui Jin |
| author_sort | Zijuan Wu |
| collection | DOAJ |
| description | Abstract Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A‐related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA‐binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL. |
| first_indexed | 2024-03-09T02:16:36Z |
| format | Article |
| id | doaj.art-2aa51661d6ae44918d00dd84d622cc75 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-09T02:16:36Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-2aa51661d6ae44918d00dd84d622cc752023-12-07T04:08:36ZengWileyAdvanced Science2198-38442023-12-011034n/an/a10.1002/advs.202304895m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic LeukemiaZijuan Wu0Xiaoling Zuo1Wei Zhang2Yongle Li3Renfu Gui4Jiayan Leng5Haorui Shen6Bihui Pan7Lei Fan8Jianyong Li9Hui Jin10Department of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaJiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment Collaborative Innovation Center for Personalized Cancer Medicine Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology Affiliated People's Hospital of Jiangsu University Zhenjiang 212002 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaDepartment of Hematology the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing Medical University Nanjing 210029 ChinaAbstract Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A‐related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA‐binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.https://doi.org/10.1002/advs.202304895chronic lymphocytic leukemiacircTET2circular RNAfatty acid oxidationHNRNPCN6‐methyladenosine (m6A) |
| spellingShingle | Zijuan Wu Xiaoling Zuo Wei Zhang Yongle Li Renfu Gui Jiayan Leng Haorui Shen Bihui Pan Lei Fan Jianyong Li Hui Jin m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia Advanced Science chronic lymphocytic leukemia circTET2 circular RNA fatty acid oxidation HNRNPC N6‐methyladenosine (m6A) |
| title | m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia |
| title_full | m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia |
| title_fullStr | m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia |
| title_full_unstemmed | m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia |
| title_short | m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia |
| title_sort | m6a modified circtet2 interacting with hnrnpc regulates fatty acid oxidation to promote the proliferation of chronic lymphocytic leukemia |
| topic | chronic lymphocytic leukemia circTET2 circular RNA fatty acid oxidation HNRNPC N6‐methyladenosine (m6A) |
| url | https://doi.org/10.1002/advs.202304895 |
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