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Hsa_circ_0007590/PTBP1 complex reprograms glucose metabolism by reducing the stability of m6A-modified PTEN mRNA in pancreatic ductal adenocarcinoma

Cancer Gene Therapy volume 31, pages 1090–1102 (2024)Cite this article

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Abstract

The role of circular RNAs (circRNAs) in glucose metabolism in pancreatic duct adenocarcinoma (PDAC) remains elusive. Through RNA sequencing of cells cultured under conditions of glucose deprivation, we identified hsa_circ_0007590. Sanger sequencing and RNase R and Act D treatments were performed to confirm the circular RNA features of hsa_circ_0007590. RNA in situ hybridization (RNA-ISH) and quantitative reverse transcription PCR (qRT-PCR) were used to estimate hsa_circ_0007590 expression in PDAC clinical specimens and cell lines. hsa_circ_0007590 expression was higher in PDAC patients and closely related to the clinicopathological characteristics of the disease. Cytoplasm‒nuclear fractionation and FISH assays demonstrated that hsa_circ_0007590 was located in the nucleus. Gain-of-function and loss-of-function assays were performed to assess the biological behaviors of PDAC cells. Seahorse XF assays were performed to validate the Warburg effect. hsa_circ_0007590 facilitated the proliferation, migration, and invasion of PDAC cells and promoted the Warburg effect. Mass spectrometry, RNA pulldown, RNA immunoprecipitation (RIP), RNA m6A quantification, m6A dot blot, MeRIP, and Western blotting were conducted to investigate the detailed mechanism through which hsa_circ_0007590 produces these effects. Mechanistically, hsa_circ_0007590 targeted PTBP1 and increased the expression of the m6A reader protein YTHDF2, leading to PTEN mRNA degradation and PI3K/AKT/mTOR pathway activation. Overall, hsa_circ_0007590, which targets PTBP1, reprograms glucose metabolism by attenuating the stability of m6A-modified PTEN mRNA and holds potential promise as a therapeutic target for PDAC.

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Fig. 1: Characterization of hsa_circ_0007590.
Fig. 2: The expression of hsa_circ_0007590 and its clinical significance in pancreatic duct adenocarcinoma (PDAC).
Fig. 3: Hsa_circ_0007590 promotes pancreatic duct adenocarcinoma (PDAC) cell proliferation in vitro and vivo.
Fig. 4: Hsa_circ_0007590 promotes pancreatic duct adenocarcinoma (PDAC) cell migration and invasion.
Fig. 5: Hsa_circ_0007590 facilitates glycolytic metabolism in pancreatic duct adenocarcinoma (PDAC).
Fig. 6: Hsa_circ_0007590 regulates the PTEN/AKT/mTOR pathway through binding PTBP1.
Fig. 7: Hsa_circ_0007590 reduced PTEN mRNA stability through YTHDF2.
Fig. 8: Hsa_circ_0007590 acts as an oncogene by upregulating YTHDF2.

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Data availability

All data that support the findings of this study are available from the corresponding authors upon reasonable request. A circRNA profiling database based on RNA sequencing data from low glucose-treated and normal glucose treated MiaPaCa-2 cells was constructed in the GEO (GSE121596).

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Acknowledgements

This study was supported by the National Natural Science Foundation of China. (No. 82203344, No. 82073150) and the Natural Science Foundation of Guangdong (No. 2021A1515010270).

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Author notes

  1. These authors contributed equally: Dandan Zheng, Wenying Chen, Juanfei Peng.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, People’s Republic of China

    Dandan Zheng, Wenying Chen, Juanfei Peng, Shineng Zhang & Yanyan Zhuang

  2. Doctor of Excellence Program (DEP), The First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China

    Dandan Zheng

  3. Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, People’s Republic of China

    Wenying Chen, Juanfei Peng, Shineng Zhang & Yanyan Zhuang

  4. Gastrointestinal Endoscopy Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, People’s Republic of China

    Xianxian Huang

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Contributions

DZ, WC, and JP conducted the majority of the experiments and interpreted of the data. XH performed some of the experiments and collected the samples. YZ and DZ wrote the manuscript. SZ and YZ conceived the study, revised the manuscript, and were responsible for research supervision and funding acquisition. All the authors have read and approved the final manuscript.

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Correspondence to Shineng Zhang or Yanyan Zhuang.

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The authors declare that they have no competing interests.

Ethics approval and consent to participate

We declare that all research activities strictly adhere to the principles outlined in the Declaration of Helsinki. This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (No. SYSEC-KY-KS-2019-128). After providing written informed consent, clinical samples and information were collected. The animal experiments were carried out according to the protocol approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University (No. SYSU-IACUC-2021-000427).

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Zheng, D., Chen, W., Peng, J. et al. Hsa_circ_0007590/PTBP1 complex reprograms glucose metabolism by reducing the stability of m6A-modified PTEN mRNA in pancreatic ductal adenocarcinoma. Cancer Gene Ther 31, 1090–1102 (2024). https://doi.org/10.1038/s41417-024-00786-4

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