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m6A modification of lipoyltransferase 1 inhibits bladder cancer progression by activating cuproptosis

Oncogene volume 43, pages 2971–2985 (2024)Cite this article

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Abstract

Cuproptosis, a cell death process caused by copper ions, is mediated by protein lipidation related to lipoic acid metabolism. There is a close connection between cuproptosis and the progression and prognosis of various tumors. Here, we identified lipoyltransferase 1 (LIPT1), a key gene related to cuproptosis, was downregulated in bladder cancer (BLCA) and was associated with unfavorable patient prognosis. Restoring the LIPT1 expression in BLCA cells suppressed the proliferation and promoted cuproptosis. Moreover, the consequences of RNA sequencing and Bodipy staining showed that the metabolic pathway mediated by LIPT1 inhibited the accumulation of lipid droplets in cells, disrupted endoplasmic reticulum (ER) homeostasis, and promoted cell apoptosis. Additionally, overexpression of LIPT1 not only repressed the proliferation rate of BLCA cells in vitro but also in vivo. Mechanistically, YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) promoted the degradation of LIPT1 mRNA in a m6A-dependent manner. In summary, these conclusions reveal that LIPT1 promotes cuprotosis and ER stress to inhibit the progression of BLCA, indicating that LIPT1 will provide a powerful treatment direction and drug target for treating BLCA.

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Fig. 1: The cuproptosis-related gene LIPTI inhibited BLCA progression and was related to the overall survival of BLCA patients.
Fig. 2: Overexpression of LIPT1 inhibited the proliferation of BLCA cells.
Fig. 3: Overexpression of LIPT1 enhanced cuproptosis.
Fig. 4: YTHDF2 mediated mRNA degradation of LIPT1 in a m6A-dependent manner.
Fig. 5: YTHDF2 inhibited cuproptosis and promoted proliferation by targeting LIPT1 in BLCA.
Fig. 6: LIPT1 promoted ER stress-mediated cell apoptosis.
Fig. 7: Enhanced endoplasmic reticulum stress contributed to the inhibition of BLCA proliferation induced by LIPT1.

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Data availability

RNA-sequencing are available at the NCBl Sequence Read Archive (SRA) under the accession number PRJNA1130104.

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Acknowledgements

This work was supported by grants from the National Natural Sciences Foundation of China (NO. 82173294 to C.H.G, NO. 82203099 to L.J.Z.), the Training Program for Middle-aged and Young Discipline Leaders of Health of Henan Province (NO. HNSWJW-2021004 to C.H.G.); the Key Program Jointly Built by Henan Province and the Ministry of Medical Science and Technology(NO.SBGJ202102127 to C.H.G. and SBGJ202102095 to F.Y.T.); the Training Program of Young and Middle-aged Health Science and Technology Innovation Excellent Youth (NO.YXKC2021033 to C.H.G.); the Program of International Training of High-level Talents of Henan Province (NO.202207 to C.H.G.); the Science and Technology Research and Development Plan Joint Foundation of Henan Province (NO. 222301420017 to C.H.G.); the Key Project of Research and Practice of Education and Teaching Reform of Zhengzhou University (NO. 2022ZZUJG082 to C.H.G.); the Professional Degree Graduate Quality Teaching Case Project of Henan Province (NO. YJS2023AL013 to C.H.G.); the Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (NO. QNCXTD2023023 to C.H.G.); the Key Technologies R & D Program of Henan Province (NO. 232102521032 to C.H.G.); the Basic Research Incubation Program for Young Teachers of Zhengzhou University (NO. JC21854035 to F.Y.T.); the Joint Construction Project between Medical Science and Technology Research Project of Henan Province (No. LHGJ20220335 to L.J.Z.); the Key Scientific Research projects of Colleges and Universities of Henan Province (NO. 24A320058 to F.Y.T.).

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  1. These authors contributed equally: Kaixuan Du, Yongbo Luo, Lei Zhang.

Authors and Affiliations

  1. Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

    Kaixuan Du, Yongbo Luo, Youmiao Zeng, Yiheng Dai, Mengda Ren, Wenbang Pan, Yuanhao Liu, Lijie Zhou & Chaohui Gu

  2. Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

    Kaixuan Du, Yongbo Luo, Youmiao Zeng, Yiheng Dai, Mengda Ren, Wenbang Pan, Yuanhao Liu, Lijie Zhou & Chaohui Gu

  3. Unit of Day Surgery Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

    Kaixuan Du, Yongbo Luo, Youmiao Zeng, Yiheng Dai, Mengda Ren, Wenbang Pan, Yuanhao Liu, Lijie Zhou & Chaohui Gu

  4. Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

    Lei Zhang

  5. Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

    Fengyan Tian

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Contributions

C.H.G., F.Y.T., and L.J.Z. conceived the study. K.X.D., Y.B.L. and L.Z. designed experiments. K.X.D., Y.B.L., and Y.M.Z. performed experiments. K.X.D., Y.B.L. and Y.H.D. assisted with animal experiments. M.D.R., Y.H.L., and W.B.P. helped to obtain BLCA patients’ clinical information. K.X.D., and Y.B.L. analyzed the data. K.X.D. wrote the manuscript and all authors reviewed and approved the manuscript for publication.

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Correspondence to Fengyan Tian, Lijie Zhou or Chaohui Gu.

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Du, K., Luo, Y., Zhang, L. et al. m6A modification of lipoyltransferase 1 inhibits bladder cancer progression by activating cuproptosis. Oncogene 43, 2971–2985 (2024). https://doi.org/10.1038/s41388-024-03139-5

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