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LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer

Cell Death & Differentiation volume 30, pages 1517–1532 (2023)Cite this article

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Abstract

Dysregulation of long noncoding RNAs (lncRNAs) has been associated with the development and progression of many human cancers. Lactate dehydrogenase A (LDHA) enzymatic activity is also crucial for cancer development, including the development of papillary thyroid cancer (PTC). However, whether specific lncRNAs can regulate LDHA activity during cancer progression remains unclear. Through screening, we identified an LDHA-interacting lncRNA, GLTC, which is required for the increased aerobic glycolysis and cell viability in PTC. GLTC was significantly upregulated in PTC tissues compared with nontumour thyroid tissues. High expression of GLTC was correlated with more extensive distant metastasis, a larger tumour size, and poorer prognosis. Mass spectrometry revealed that GLTC, as a binding partner of LDHA, promotes the succinylation of LDHA at lysine 155 (K155) via competitive inhibition of the interaction between SIRT5 and LDHA, thereby promoting LDHA enzymatic activity. Overexpression of the succinylation mimetic LDHAK155E mutant restored glycolytic metabolism and cell viability in cells in which metabolic reprogramming and cell viability were ceased due to GLTC depletion. Interestingly, GLTC inhibition abrogated the effects of K155-succinylated LDHA on radioiodine (RAI) resistance in vitro and in vivo. Taken together, our results indicate that GLTC plays an oncogenic role and is an attractive target for RAI sensitisation in PTC treatment.

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Fig. 1: GLTC is clinically relevant in PTC.
Fig. 2: GLTC-induced cell viability depends on glycolytic metabolism.
Fig. 3: GLTC directly binds to LDHA and increases LDHA activity.
Fig. 4: GLTC-induced succinylation of LDHA at K155 increases its enzymatic activity in PTC cells.
Fig. 5: The GLTC/LDHA interaction disrupts SIRT5-mediated regulation of LDHA succinylation at K155.
Fig. 6: LDHA succinylation at K155 mediates the biological function of GLTC in PTC cells.
Fig. 7: Succinylation of LDHA-K155 by GLTC promotes 131I resistance in PTC cells.
Fig. 8: Working model of the role of GLTC in regulating LDHA-mediated PTC progression and RAI resistance.

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Data availability

All data generated or analysed during this study are included in this published paper and its supplementary information files. RNA-Seq data have been deposited in NCBI SRA database (PRJNA857849).

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82001865), the National Thyroid Research Project for Chinese Young and Middle-aged Doctors (2020), the Natural Science Foundation of Jiangsu Province (BK20200145).

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  1. These authors contributed equally: Liang Shi, Rui Duan, Zhenhua Sun.

Authors and Affiliations

  1. Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Liang Shi, Rui Duan, Wenyu Wu, Feng Wang & Xue Xue

  2. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Rui Duan

  3. Department of Thyroid and Breast Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Zhenhua Sun

  4. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Qiong Jia

  5. Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, Shanghai, China

    Jianjun Liu

  6. Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Hao Zhang

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Contributions

XX, HZ and JL conceived and designed the study. FW and JL supervised the study. LS, RD, XX and QJ performed the experiments and prepared the figures. LS and RD performed the statistical analysis. HZ, LS, ZS and WW contributed to the acquisition, analysis, or interpretation of the data. LS, ZS and RD contributed materials. XX, LS and RD drafted the paper. All authors read and approved the final paper.

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Correspondence to Jianjun Liu, Hao Zhang or Xue Xue.

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The studies involving human participants were reviewed and approved by the Institutional Ethics Committees of the Affiliated Hospital of Jiangsu University, School of Medicine, Jiangsu University and Nanjing First Hospital, Nanjing Medical University. All participants provided informed consent, and their privacy was fully protected. All animal experiments were performed in accordance with the guidelines provided by the Animal Ethics Committee of Nanjing First Hospital (DWSY-22105231).

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Shi, L., Duan, R., Sun, Z. et al. LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer. Cell Death Differ 30, 1517–1532 (2023). https://doi.org/10.1038/s41418-023-01157-6

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