CDK13 drives clear cell renal carcinoma through METTL16-mediated m6A modification of ACLY mRNA
CDK13 drives clear cell renal carcinoma through METTL16-mediated m6A modification of ACLY mRNA
Chen Jinsuo(Affiliated Hospital of Hebei University); Liu Huan(The First Central Hospital of Baoding); Zhang Yong(Chinese Academy of Medical Sciences and Peking Union Medical College); Gu Junfei(The Second Hospital of Hebei Medical University); Wu Xiaoli(The Second Hospital of Hebei Medical University); Xuan Fan(The Second Hospital of Hebei Medical University); Qu Changbao(Shijiazhuang People’s Hospital); Sun Hao(Hebei Medical University); Yue Nanxi(Hebei Medical University); Yang Chenxiao(The Affiliated Hospital of Qingdao University); Zhao Hongye(Hebei Medical University); Yang Wenzeng(Affiliated Hospital of Hebei University); Yang Zhan(The Affiliated Hospital of Qingdao University)
58권, 472~486쪽
초록
Cyclin-dependent kinase 13 (CDK13) has emerged as a critical regulator of oncogenic metabolism, but its role in rewiring lipid metabolism in clear cell renal cell carcinoma (ccRCC) remains undefined. Here we identify CDK13 as a master orchestrator of lipid dysregulation in ccRCC, demonstrating that it drives de novo lipogenesis through a phosphorylation-dependent RNA N6-methyladenosine (m6A) modification axis. Clinically, CDK13 overexpression correlates with advanced tumor stage, poor prognosis and aberrant lipid accumulation in patient-derived ccRCC tissues. Mechanistically, CDK13 directly phosphorylates the methyltransferase-like protein 16 (METTL16) at Ser329, augmenting its catalytic activity to install m6A modifications on ATP-citrate synthase (ACLY) messenger RNA. These m6A marks are selectively recognized by the YTHDC2 reader protein, leading to mRNA stabilization and increased acetyl-CoA production, which fuels lipogenesis and sustains ccRCC aggressiveness. Genetic or pharmacological disruption of the CDK13–METTL16–ACLY axis synergistically suppresses lipid deposition, tumor growth and metastasis in vitro and in vivo. Notably, targeting CDK13 with the small-molecule inhibitor 1NM-PP1 potentiates METTL16 depletion-mediated anticancer effects. Our findings establish a kinase-RNA modifier axis that links CDK13 to epitranscriptomic control of lipid metabolism, positioning the CDK13–METTL16–ACLY pathway as a promising target for precision therapies against ccRCC.
Abstract
Cyclin-dependent kinase 13 (CDK13) has emerged as a critical regulator of oncogenic metabolism, but its role in rewiring lipid metabolism in clear cell renal cell carcinoma (ccRCC) remains undefined. Here we identify CDK13 as a master orchestrator of lipid dysregulation in ccRCC, demonstrating that it drives de novo lipogenesis through a phosphorylation-dependent RNA N6-methyladenosine (m6A) modification axis. Clinically, CDK13 overexpression correlates with advanced tumor stage, poor prognosis and aberrant lipid accumulation in patient-derived ccRCC tissues. Mechanistically, CDK13 directly phosphorylates the methyltransferase-like protein 16 (METTL16) at Ser329, augmenting its catalytic activity to install m6A modifications on ATP-citrate synthase (ACLY) messenger RNA. These m6A marks are selectively recognized by the YTHDC2 reader protein, leading to mRNA stabilization and increased acetyl-CoA production, which fuels lipogenesis and sustains ccRCC aggressiveness. Genetic or pharmacological disruption of the CDK13–METTL16–ACLY axis synergistically suppresses lipid deposition, tumor growth and metastasis in vitro and in vivo. Notably, targeting CDK13 with the small-molecule inhibitor 1NM-PP1 potentiates METTL16 depletion-mediated anticancer effects. Our findings establish a kinase-RNA modifier axis that links CDK13 to epitranscriptomic control of lipid metabolism, positioning the CDK13–METTL16–ACLY pathway as a promising target for precision therapies against ccRCC.
- 발행기관:
- 생화학분자생물학회
- 분류:
- 생화학