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Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma

Cell Death & Differentiation (2024)Cite this article

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Abstract

Dysregulation of histone supply is implicated in various cancers, including lung adenocarcinoma (LUAD), although the underlying mechanisms remain poorly understood. Here, we demonstrate that knockout of Fbxo45 in mouse alveolar epithelial type 2 (AT2) cells leads to spontaneous LUAD. Our findings reveal that FBXO45 is a novel cell-cycle-regulated protein that is degraded upon phosphorylation by CDK1 during the S/G2 phase. During the S phase or DNA damage repair, FBXO45 binds to UPF1 and recruits the phosphatase PPP6C, thereby inhibiting UPF1 phosphorylation. This process is crucial for preventing the degradation of replication-dependent (RD) histone mRNAs and ensuring an adequate histone supply. In the absence of FBXO45, the impaired interaction between PPP6C and UPF1 results in sustained hyperphosphorylation of UPF1 throughout the cell cycle, leading to an insufficient histone supply, chromatin relaxation, genomic instability, and an increased rate of gene mutations, ultimately culminating in malignant transformation. Notably, analysis of clinical LUAD specimens confirms a positive correlation between the loss of FBXO45 and genomic instability, which is consistent with our findings in the mouse model. These results highlight the critical role of FBXO45 as a genomic guardian in coordinating histone supply and DNA replication, providing valuable insights into potential therapeutic targets and strategies for the treatment of LUAD.

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Fig. 1: Fbxo45 deficiency in AT2 cells leads to LUAD.
Fig. 2: Fbxo45 deficiency reduces the supply of RD-histones.
Fig. 3: FBXO45 prevents rapid degradation of RD-histone mRNAs.
Fig. 4: FBXO45 binds to UPF1 and inhibits pS/TQ-UPF1.
Fig. 5: FBXO45 reduces the phosphorylation level of UPF1 by recruiting PPP6C to UPF1.
Fig. 6: FBXO45 is a cell-cycle regulated protein and highly expressed in the S phase.
Fig. 7: Fbxo45 deficiency leads to loosened chromatin and impaired DDR.
Fig. 8: Fbxo45 deficiency leads to accumulation of gene mutations.

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Data availability

The RNA-Seq data generated in this study were provided as EXCEL profiles in Supplementary Data and have been deposited in the Gene Expression Omnibus (GEO) repository under the accession number GSE218662. The whole-exome sequencing (WES) data generated in this study were provided as EXCEL profiles in Supplementary Data and have been deposited in the Sequence Read Archive (SRA) database under the accession number PRJNA905170. The mass spectrometry data generated in this study were provided as EXCEL profiles in Supplementary Data and have been uploaded to the Integrated Proteome Resources (iProX) database under the accession number IPX0005469000 and IPX0010103000. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All data are also available from the corresponding author (J.Y.) upon reasonable request.

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Acknowledgements

We thank the Proteomics, Electron microscope and Flow sorting laboratory of Core Facility, Shanghai Jiao Tong University College of Basic Medical Sciences.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82230100, 32271310, 82273138) and Natural Science Foundation of Shanghai (23ZR1411500).

Author information

Author notes

  1. These authors contributed equally: Lian Li, Junya Li, Ran Chen, Caihu Huang, Yong Zuo.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Cell Biology & Department of Thoracic Surgery Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Lian Li, Junya Li, Ran Chen, Caihu Huang, Yong Zuo, Runhui Lu, Xiaojia Liu, Jiayi Huang, Yanli Wang, Xian Zhao, Jinke Cheng, Xiaojing Zhao & Jianxiu Yu

  2. Department of Respiratory and Critical Care Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 201700, China

    Lian Li, Chunling Du & Jianxiu Yu

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  1. Lian Li
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Contributions

JY and LL conceptualized the project; LL, JL, RC, CH, YZ and JC designed the methods; LL, JL, RC, CH, RL, XL, and JH performed most of experiments; LL, YW, XZ and JY performed formal analyses; LL and JY wrote the manuscript; JY, CD, and XJZ supervised the project. All authors reviewed and edited the manuscript.

Corresponding authors

Correspondence to Xiaojing Zhao, Chunling Du or Jianxiu Yu.

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The authors declare no competing interests.

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Animal experiments were conducted following the general rules for the care and use of experimental animals and approved by the Shanghai Jiao Tong University School of Medicine Animal Care and Use Committee (permission no. A-2022-036). Clinical samples were collected from patients with written informed consent, following a protocol approved by The Affiliated Renji Hospital of Shanghai Jiao Tong University School of Medicine (ethics approval no. RA-2022-267).

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Li, L., Li, J., Chen, R. et al. Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01433-z

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