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m6A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation

Cell Death & Differentiation volume 31, pages 1029–1043 (2024)Cite this article

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Abstract

Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N6-methyladenosine (m6A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m6A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m6A modification levels. Increasing m6A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m6A modification had an opposite effect. Integrated m6A-seq and RNA-seq revealed potential targets of m6A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m6A-YTHDF2-dependent manner through reducing m6A modification in its exon1 and 5’-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m6A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy.

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Fig. 1: m6A regulates hepatoma cell necrosis under glucose deprivation.
Fig. 2: FOSL1 is a target of m6A and upregulated in an m6A-dependent manner under glucose deprivation.
Fig. 3: YTHDF2 binds to m6A-modified FOSL1 mRNA to regulate its decay under glucose deprivation.
Fig. 4: FOSL1 protects hepatoma cells against necrosis under glucose deprivation.
Fig. 5: FOSL1 suppresses ATF3 by direct promoter binding in glucose-deprived hepatoma cells.
Fig. 6: ATF3 competes with NRF2 for binding to ARE to inhibit NRF2 transcriptional activity in glucose-deprived hepatoma cells.

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Data availability

The raw sequence data produced in this study have been deposited in the Genome Sequence Archive of the National Genomics Data Center, China National Center for Bioinformation. These raw data are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human using the following accession numbers: MeRIP-seq, HRA007033; RNA-seq, HRA007034; ChIP-seq, HRA007037. All uncropped western blots involved in this study have been placed in the supplementary files. Any additional data required to reanalyze the results reported in this paper are available from the corresponding author upon request.

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Acknowledgements

The authors sincerely thank Drs. Xing-Xian Guo and Yan-Ping Li (Centre for Lipid Research, the Second Affiliated Hospital of Chongqing Medical University) for their help in experimental methods. Meanwhile, the authors sincerely thank Dr. Feng Qi, Miss Min-Jie Zhao, Mr Yi-Fan Zhang, and Mr Yue-Zhou Zhang (Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University) for their warm help during the study. In addition, The authors sincerely thank Prof. Yong Zhao (Department of Nutrition and Food Hygiene, School of Public Health and Management of Chongqing Medical University) for his warm help in statistical analyses. 

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant number 82203391), China Postdoctoral Science Foundation (Project number: 2021M700638), and the Special Funding for Postdoctoral Research Project of Chongqing (Grant No. 2021XM2043). The funding supporters had no role in study design, data acquisition and analysis, decision to publish, or the preparation of the manuscript.

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  1. These authors contributed equally: Chun-Rui Wang, Jun-Hua Gong.

Authors and Affiliations

  1. Department of Infectious Diseases, Institute for Viral Hepatitis, the Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Chun-Rui Wang

  2. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Jun-Hua Gong, Zhi-Bo Zhao, Bian Shu, Jie-Jun Hu, Dong Cai, Xin-Yi Liu, Xin Dai, Jian-Ping Gong & Guo-Chao Zhong

  3. Department of Nutrition and Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China

    Qian Zhu

  4. Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Chan Qiu

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Contributions

CRW and GCZ conceived the study idea. CRW was responsible for experiment design and data analyses. JHG, QZ, ZBZ, and BS performed all experiments. JJH and DC collected tumor sample. GCZ was responsible for experiment guidance and funding acquisition, and supervised the study. CRW drafted the initial manuscript. CRW, JHG, and GCZ interpreted the results of experiments and statistical analyses together. All authors made critical comments and revisions for the initial manuscript. All authors approved the final version of the article, including the authorship list.

Corresponding author

Correspondence to Guo-Chao Zhong.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Boards of the Second Affiliated Hospital of Chongqing Medical University (approval numbers RER2021-036 and RER2022-237). Written informed consents were obtained from all included patients.

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Supplementary information

Supplementary figures

Supplementary methods and materials

Table S1. Individual and common genes in glucose deprivation and high glucose groups

Table S2. Analysis results of MeRIP-seq data

41418_2024_1308_MOESM5_ESM.docx

Table S3. The KEGG pathway enrichment analysis of the significant differential peak-associated genes between glucose-deprived hepatoma cells and control cells

Table S4. Analysis results of RNA-seq data.

Table S5. Comparisons of clinicopathologic characteristics between groups with high and low FOSL1 expression

Table S6. ChIP-seq-identified genes whose FOSL1 binding peaks were located within the promoter region

Table S7. Oligonucleotide sequences used in the present study

Table S8. The specific information of antibodies used in the current study

Table S9. The specific information of main reagents used in the current study

Original western blot image

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Wang, CR., Gong, JH., Zhao, ZB. et al. m6A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation. Cell Death Differ 31, 1029–1043 (2024). https://doi.org/10.1038/s41418-024-01308-3

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