NAT10 mediated ac4C acetylation driven m 6 A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma.

Autor: Mei Z; Department 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 University, Harbin, China., Shen Z; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China., Pu J; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China., Liu Q; Department 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 University, Harbin, China., Liu G; Department 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 University, Harbin, China., He X; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China., Wang Y; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China., Yue J; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China., Ge S; Department 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 University, Harbin, China., Li T; Department 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 University, Harbin, China., Yuan Y; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China. yuanye_hmu@126.com.; National Key Laboratory of Frigid Cardiovascular Disease, Harbin, China. yuanye_hmu@126.com.; Department of Pharmacy, (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China. yuanye_hmu@126.com., Yang L; Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China. yangray83@vip.qq.com.; Key Laboratory of Hepatosplenic Surgery of Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. yangray83@vip.qq.com.; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China. yangray83@vip.qq.com.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jan 17; Vol. 22 (1), pp. 51. Date of Electronic Publication: 2024 Jan 17.
DOI: 10.1186/s12964-023-01321-y
Abstrakt: The dynamic changes of RNA N6-methyladenosine (m 6 A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m 6 A 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 m 6 A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m 6 A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m 6 A 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 m 6 A 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 m 6 A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m 6 A-LDHA/PFKM in osteosarcoma. Video Abstract.
(© 2024. The Author(s).)
Databáze: MEDLINE
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