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- Title
NAT10 mediated ac4C acetylation driven m<sup>6</sup>A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma.
- Authors
Mei, Zhongting; Shen, Zhihua; Pu, Jiaying; Liu, Qian; Liu, Guoxin; He, Xuting; Wang, Yang; Yue, Jinrui; Ge, Shiyu; Li, Tao; Yuan, Ye; Yang, Lei
- 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. 6WoSibQBSZGZLQEcMB75Lw Video Abstract
- Subjects
GLYCOLYSIS; OSTEOSARCOMA; ACETYLATION; RNA modification &; restriction; LACTATE dehydrogenase; PROTEIN stability; MONOCARBOXYLATE transporters
- Publication
Cell Communication & Signaling, 2024, Vol 22, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-023-01321-y