NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma
Abstract The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have iden...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-023-01321-y |
| _version_ | 1797349786580418560 |
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| author | Zhongting Mei Zhihua Shen Jiaying Pu Qian Liu Guoxin Liu Xuting He Yang Wang Jinrui Yue Shiyu Ge Tao Li Ye Yuan Lei Yang |
| author_facet | Zhongting Mei Zhihua Shen Jiaying Pu Qian Liu Guoxin Liu Xuting He Yang Wang Jinrui Yue Shiyu Ge Tao Li Ye Yuan Lei Yang |
| author_sort | Zhongting Mei |
| collection | DOAJ |
| description | Abstract The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m6A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m6A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m6A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m6A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m6A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma. Video Abstract |
| first_indexed | 2024-03-08T12:35:28Z |
| format | Article |
| id | doaj.art-78bec7fc68504b9184354cedba69468b |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-08T12:35:28Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-78bec7fc68504b9184354cedba69468b2024-01-21T12:28:20ZengBMCCell Communication and Signaling1478-811X2024-01-0122111410.1186/s12964-023-01321-yNAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcomaZhongting Mei0Zhihua Shen1Jiaying Pu2Qian Liu3Guoxin Liu4Xuting He5Yang Wang6Jinrui Yue7Shiyu Ge8Tao Li9Ye Yuan10Lei Yang11Department of Pharmacology, (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Pharmacology, (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityDepartment of Pharmacology, (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Pharmacology, (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityDepartment of Pharmacology, (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityDepartment of Clinical Pharmacology, College of Pharmacy, Harbin Medical UniversityDepartment of Orthopedics, The First Affiliated Hospital of Harbin Medical UniversityAbstract The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m6A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m6A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m6A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m6A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m6A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma. Video Abstracthttps://doi.org/10.1186/s12964-023-01321-yOsteosarcomaac4C acetylationm6A methylationNAT10GlycolysisYTHDC1 |
| spellingShingle | Zhongting Mei Zhihua Shen Jiaying Pu Qian Liu Guoxin Liu Xuting He Yang Wang Jinrui Yue Shiyu Ge Tao Li Ye Yuan Lei Yang NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma Cell Communication and Signaling Osteosarcoma ac4C acetylation m6A methylation NAT10 Glycolysis YTHDC1 |
| title | NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma |
| title_full | NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma |
| title_fullStr | NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma |
| title_full_unstemmed | NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma |
| title_short | NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma |
| title_sort | nat10 mediated ac4c acetylation driven m6a modification via involvement of ythdc1 ldha pfkm regulates glycolysis and promotes osteosarcoma |
| topic | Osteosarcoma ac4C acetylation m6A methylation NAT10 Glycolysis YTHDC1 |
| url | https://doi.org/10.1186/s12964-023-01321-y |
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