Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The Ku70-SIX1-GPT2 axis regulates alpha-ketoglutarate metabolism to drive progression of prostate cancer

Oncogene volume 44, pages 92–104 (2025)Cite this article

Subjects

Abstract

Sine oculis homeobox homolog 1 (SIX1) is a new identified cancer driver in the development of prostate cancer (PC). However, the upstream regulatory mechanisms for SIX1 reactivation in cancer remains elusive. Here, we found that Ku70 robustly interacts with SIX1 in the nucleus of PC cells. The HD ___domain of SIX1 and the DBD ___domain of Ku70 are required for formation of Ku70-SIX1 complex. 20 groups of hydrogen bonds were identified in this complex by molecular dynamics simulation. Depletion of Ku70/SIX1 notably abrogates the proliferation and migration of PC. Further studies revealed that SIX1 is recruited to the promoter region on glutamate-pyruvate transaminase 2 (GPT2). Ku70 enhances the SIX1-mediated transcriptional activation on GPT2, thereby facilitating the generation of alpha-ketoglutarate (α-KG). In addition, formation of the Ku70-SIX1 complex promotes GPT2-dependent cell proliferation and migration in PC. Moreover, the expression of GPT2 is upregulated and strongly correlated with the expression of Ku70/SIX1 in PC tissues. In summary, our findings not only provide insight into the mechanistic interactions between Ku70 and SIX1, but also highlight the significance of the Ku70-SIX1-GPT2 axis for α-KG metabolism and PC carcinogenesis.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Ku70 physically interacts with SIX1 in PC cells.
Fig. 2: The potential binding ___domain of Ku70 and SIX1.
Fig. 3: The silence of Ku70 or SIX1 suppresses the proliferation of PC in vitro and in vivo.
Fig. 4: Depletion of Ku70 or SIX1 restrains the metastatic activity of PC in vitro and in vivo.
Fig. 5: Identification of GPT2 as a critical target of the Ku70-SIX1 complex.
Fig. 6: Ku70 strengthens the SIX1-mediated GPT2 transcription.
Fig. 7: GPT2 mediates the tumor-promoting effect of the Ku70-SIX1 complex.
Fig. 8: The association of Ku70, SIX1, and GPT2 expression in PC tissues.

Similar content being viewed by others

Data availability

All datasets and materials presented in this study are available from the corresponding author on reasonable request.

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clinicians. 2024;74:229–63.

    Article  Google Scholar 

  2. Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK, et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature. 2016;533:547–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sullivan WJ, Mullen PJ, Schmid EW, Flores A, Momcilovic M, Sharpley MS, et al. Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization. Cell. 2018;175:117–32.e21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vriens K, Christen S, Parik S, Broekaert D, Yoshinaga K, Talebi A, et al. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature. 2019;566:403–6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mossmann D, Müller C, Park S, Ryback B, Colombi M, Ritter N, et al. Arginine reprograms metabolism in liver cancer via RBM39. Cell. 2023;186:5068–83.e23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ricci L, Stanley FU, Eberhart T, Mainini F, Sumpton D, Cardaci S. Pyruvate transamination and NAD biosynthesis enable proliferation of succinate dehydrogenase-deficient cells by supporting aerobic glycolysis. Cell Death Dis. 2023;14:403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li N, Xu X, Liu D, Gao J, Gao Y, Wu X, et al. The delta subunit of the GABA(A) receptor is necessary for the GPT2-promoted breast cancer metastasis. Theranostics. 2023;13:1355–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mitra D, Vega-Rubin-de-Celis S, Royla N, Bernhardt S, Wilhelm H, Tarade N, et al. Abrogating GPT2 in triple-negative breast cancer inhibits tumor growth and promotes autophagy. Int J Cancer. 2021;148:1993–2009.

    Article  CAS  PubMed  Google Scholar 

  9. Li J, Qin Z, Li Y, Huang B, Xiao Q, Chen P, et al. Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer. Adv Sci. 2024;11:e2310208.

    Article  Google Scholar 

  10. Zarei M, Hajihassani O, Hue JJ, Loftus AW, Graor HJ, Nakazzi F, et al. IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer. Cancer Res. 2024;84:3072–85.

  11. Li JJ, Yu T, Zeng P, Tian J, Liu P, Qiao S, et al. Wild-type IDH2 is a therapeutic target for triple-negative breast cancer. Nat Commun. 2024;15:3445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Spitz F, Demignon J, Porteu A, Kahn A, Concordet JP, Daegelen D, et al. Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site. Proc Natl Acad Sci USA. 1998;95:14220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247–54.

    Article  CAS  PubMed  Google Scholar 

  14. Li L, Liang Y, Kang L, Liu Y, Gao S, Chen S, et al. Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer Cell. 2018;33:368–85.e7.

    Article  CAS  PubMed  Google Scholar 

  15. Liu Y, Kong WY, Yu CF, Shao ZL, Lei QC, Deng YF, et al. SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta Pharmacologica Sin. 2023;44:853–64.

    Article  CAS  Google Scholar 

  16. Liao Y, Liu Y, Shao Z, Xia X, Deng Y, Cai J, et al. A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene. 2021;40:4291–306.

    Article  CAS  PubMed  Google Scholar 

  17. Chu Y, Jiang M, Wu N, Xu B, Li W, Liu H, et al. O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation. Theranostics. 2020;10:9830–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, et al. Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut. 2021;70:900–14.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu Z, Rong Z, Luo Z, Yu Z, Zhang J, Qiu Z, et al. Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis. Mol Cancer. 2019;18:126.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liao Y, Sun W, Shao Z, Liu Y, Zhong X, Deng Y, et al. A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. Int J Biol Sci. 2022;18:2439–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Al-Ubaidi FL, Schultz N, Loseva O, Egevad L, Granfors T, Helleday T. Castration therapy results in decreased Ku70 levels in prostate cancer. Clin Cancer Res. 2013;19:1547–56.

    Article  CAS  PubMed  Google Scholar 

  22. Jin S, Weaver DT. Double-strand break repair by Ku70 requires heterodimerization with Ku80 and DNA binding functions. EMBO J. 1997;16:6874–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang Q, Xu J, Gu J, Shi H, Zhang J, Zhang J, et al. Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications. Adv Sci. 2022;9:e2201609.

    Article  Google Scholar 

  24. Wang X, Liu R, Zhu W, Chu H, Yu H, Wei P, et al. UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis. Nature. 2019;571:127–31.

    Article  CAS  PubMed  Google Scholar 

  25. Kim M, Gwak J, Hwang S, Yang S, Jeong SM. Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism. Oncogene. 2019;38:4729–38.

    Article  CAS  PubMed  Google Scholar 

  26. Wang CA, Jedlicka P, Patrick AN, Micalizzi DS, Lemmer KC, Deitsch E, et al. SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Investig. 2012;122:1895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iwanaga R, Wang CA, Micalizzi DS, Harrell JC, Jedlicka P, Sartorius CA, et al. Expression of Six1 in luminal breast cancers predicts poor prognosis and promotes increases in tumor initiating cells by activation of extracellular signal-regulated kinase and transforming growth factor-beta signaling pathways. Breast Cancer Res. 2012;14:R100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu K, Li Z, Cai S, Tian L, Chen K, Wang J, et al. EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. Cancer Res. 2013;73:4488–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hsu JY, Danis EP, Nance S, O’Brien JH, Gustafson AL, Wessells VM, et al. SIX1 reprograms myogenic transcription factors to maintain the rhabdomyosarcoma undifferentiated state. Cell Rep. 2022;38:110323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu W, Gao M, Li L, Chen Y, Fan H, Cai Q, et al. Homeoprotein SIX1 compromises antitumor immunity through TGF-β-mediated regulation of collagens. Cell Mol Immunol. 2021;18:2660–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Park SJ, Ciccone SL, Freie B, Kurimasa A, Chen DJ, Li GC, et al. A positive role for the Ku complex in DNA replication following strand break damage in mammals. J Biol Chem. 2004;279:6046–55.

    Article  CAS  PubMed  Google Scholar 

  32. Rivera-Calzada A, Spagnolo L, Pearl LH, Llorca O. Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs. EMBO Rep. 2007;8:56–62.

    Article  CAS  PubMed  Google Scholar 

  33. Li Q, Yao H, Wang Y, Wu Y, Thorne RF, Zhu Y, et al. circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells. Cell Rep. 2022;41:111707.

    Article  CAS  PubMed  Google Scholar 

  34. Yu Y, Liu T, Yu G, Wang H, Du Z, Chen Y, et al. PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair. Cell Death Dis. 2022;13:978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang B, Xie M, Li R, Owonikoko TK, Ramalingam SS, Khuri FR, et al. Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. Cell Death Differ. 2014;21:1160–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shu Y, Jin X, Ji M, Zhang Z, Wang X, Liang H, et al. Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis. Cancer Res. 2024;84:2836–55.

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (82072810, 82373327), Plan on enhancing scientific research in Guangzhou Medical University, Cultivation Program of National Natural Science Foundation for Distinguished Young Scholars of Guangzhou Medical University (JP2022002), Innovation team of general Universities in Guangdong Province (2022KCXTD021), Discipline Construction Funds of Guangzhou Medical University (JCXKJS2022A06), Guangdong Basic and Applied Basic Research Foundation (2021A1515111087), Medical research project of Foshan Health Bureau (20220479).

Author information

Author notes

  1. These authors contributed equally: Hongbiao Huang, Xuefen Zhuang, Shusha Yin.

Authors and Affiliations

  1. Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China

    Hongbiao Huang, Xuefen Zhuang, Shusha Yin, Xiaohong Xia & Yuning Liao

  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Hongbiao Huang, Xuefen Zhuang, Shusha Yin, Wenshuang Sun, Ji Cheng, E-ying Peng, Yujie Xiang, Xiaoyue He, Mengfan Tang, Yuting Li, Yu Yao, Zhenlong Shao & Yuning Liao

  3. Department of Pathology, The First People’s Hospital of Foshan, Foshan, 528000, China

    Yuanfei Deng & Qing Liu

  4. Department of Breast Surgery, The First People’s Hospital of Foshan, Foshan, 528000, China

    Gengxi Cai

Authors
  1. Hongbiao Huang
    View author publications

    Search author on:PubMed Google Scholar

  2. Xuefen Zhuang
    View author publications

    Search author on:PubMed Google Scholar

  3. Shusha Yin
    View author publications

    Search author on:PubMed Google Scholar

  4. Wenshuang Sun
    View author publications

    Search author on:PubMed Google Scholar

  5. Ji Cheng
    View author publications

    Search author on:PubMed Google Scholar

  6. E-ying Peng
    View author publications

    Search author on:PubMed Google Scholar

  7. Yujie Xiang
    View author publications

    Search author on:PubMed Google Scholar

  8. Xiaoyue He
    View author publications

    Search author on:PubMed Google Scholar

  9. Mengfan Tang
    View author publications

    Search author on:PubMed Google Scholar

  10. Yuting Li
    View author publications

    Search author on:PubMed Google Scholar

  11. Yu Yao
    View author publications

    Search author on:PubMed Google Scholar

  12. Yuanfei Deng
    View author publications

    Search author on:PubMed Google Scholar

  13. Qing Liu
    View author publications

    Search author on:PubMed Google Scholar

  14. Zhenlong Shao
    View author publications

    Search author on:PubMed Google Scholar

  15. Xiaohong Xia
    View author publications

    Search author on:PubMed Google Scholar

  16. Gengxi Cai
    View author publications

    Search author on:PubMed Google Scholar

  17. Yuning Liao
    View author publications

    Search author on:PubMed Google Scholar

Contributions

HBH, XFZ, and SSY contributed equally to this work. YNL, GXC, and HBH conceived the ideas and designed the experiments. HBH, XFZ, SSY, WSS, JC, EYP, YJX, XYH, MFT, YTL, YY, YFD, QL, ZLS, XHX, and GXC performed the experiments. YNL and HBH wrote the manuscript.

Corresponding authors

Correspondence to Hongbiao Huang, Gengxi Cai or Yuning Liao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all the subjects. All animal experiments were approved by the institutional animal care and use committees of Guangzhou Medical University(GY2022-137). All human subjects were performed with the approval of the Medical Ethics Committee of the First People’s Hospital of Foshan (ethics approval number: L [2024] No. 3).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Zhuang, X., Yin, S. et al. The Ku70-SIX1-GPT2 axis regulates alpha-ketoglutarate metabolism to drive progression of prostate cancer. Oncogene 44, 92–104 (2025). https://doi.org/10.1038/s41388-024-03209-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03209-8

Search

Advanced search

Quick links