Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A
- PMID: 38118002
- PMCID: PMC10954454
- DOI: 10.1093/nar/gkad1193
Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A
Abstract
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
Figures








References
-
- Barbieri I., Kouzarides T. Role of RNA modifications in cancer. Nat. Rev. Cancer. 2020; 20:303–322. - PubMed
-
- Boriack-Sjodin P.A., Ribich S., Copeland R.A. RNA-modifying proteins as anticancer drug targets. Nat. Rev. Drug Discov. 2018; 17:435–453. - PubMed
-
- Han X., Wang M., Zhao Y.L., Yang Y., Yang Y.G. RNA methylations in human cancers. Semin. Cancer Biol. 2021; 75:97–115. - PubMed
MeSH terms
Substances
Grants and funding
- 82373298/National Natural Science Foundation of China
- 20DZ2270800/Science and Technology Commission of Shanghai
- 2023M732290/China Postdoctoral Science Foundation
- 2022ZZ01003/Shanghai Key Clinical Specialty, Shanghai Eye Disease Research Center
- SHSMU-ZDCX20210900/Innovative Research Team of High-level Local Universities in Shanghai
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases