m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.

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  • Additional Information
    • Source:
      Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Weinheim : WILEY-VCH, [2014]-
    • Subject Terms:
      Carcinoma, Renal Cell*/metabolism ; Carcinoma, Renal Cell*/genetics ; Carcinoma, Renal Cell*/pathology ; Kidney Neoplasms*/metabolism ; Kidney Neoplasms*/genetics ; Kidney Neoplasms*/pathology ; Phosphatidic Acids*/metabolism ; Disease Progression*; Humans ; Mice ; Animals ; Phosphatidate Phosphatase/metabolism ; Phosphatidate Phosphatase/genetics ; Cell Line, Tumor ; Methyltransferases/metabolism ; Methyltransferases/genetics ; Disease Models, Animal
    • Abstract:
      N6-methyl-2'-O-methyladenosine (m6Am), occurring adjacent to the 7-methylguanosine (m7G) cap structure and catalyzed by the newly identified writer PCIF1 (phosphorylated CTD interacting factor 1), has been implicated in the pathogenesis of various diseases. However, its involvement in renal cell carcinoma (RCC) remains unexplored. Here, significant upregulation of PCIF1 and m6Am levels in RCC tissues are identified, unveiling their oncogenic roles both in vitro and in vivo. Mechanically, employing m6Am-Exo-Seq, LPP3 (phospholipid phosphatase 3) mRNA is identified as a key downstream target whose translation is enhanced by m6Am modification. Furthermore, LPP3 is revealed as a key regulator of phosphatidic acid metabolism, critical for preventing its accumulation in mitochondria and facilitating mitochondrial fission. Consequently, Inhibition of the PCIF1/LPP3 axis significantly altered mitochondrial morphology and reduced RCC tumor progression. In addition, depletion of PCIF1 sensitizes RCC to sunitinib treatment. This study highlights the intricate interplay between m6Am modification, phosphatidic acid metabolism, and mitochondrial dynamics, offering a promising therapeutic avenue for RCC.
      (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
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    • Grant Information:
      82173221 National Natural Science Foundation of China; 82303202 National Natural Science Foundation of China; 82072809 National Natural Science Foundation of China; 82472720 National Natural Science Foundation of China; 82372687 National Natural Science Foundation of China; 2024C03045 "Pioneer" and "Leading Goose" R&D Program of Zhejiang Province; LHDMZ23H160004 Zhejiang Provincial Natural Science Foundation of China
    • Contributed Indexing:
      Keywords: N6,2′‐O‐dimethyladenosine; PCIF1; mitochondrial dynamics; phosphatidic acid metabolism; renal cell carcinoma
    • Accession Number:
      0 (Phosphatidic Acids)
      EC 3.1.3.4 (Phosphatidate Phosphatase)
      EC 2.1.1.- (Methyltransferases)
    • Publication Date:
      Date Created: 20241018 Date Completed: 20241211 Latest Revision: 20241213
    • Publication Date:
      20241213
    • Accession Number:
      PMC11633504
    • Accession Number:
      10.1002/advs.202404033
    • Accession Number:
      39422663