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:

p52-ZER6/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy

Oncogene (2024)Cite this article

Subjects

Abstract

Cancer stem cells (CSCs), which are distinct subpopulations of tumor cells, have a substantially higher tumor-initiating capacity and are closely related to poor clinical outcomes. Damage to organelles can trigger CSC pool exhaustion; however, the underlying mechanisms are poorly understood. ZER6 is a zinc-finger protein with two isoforms possessing different amino termini: p52-ZER6 and p71-ZER6. Since their discovery, almost no study reported on their biological and pathological functions. Herein, we found that p52-ZER6 was crucial for CSC population maintenance; p52-ZER6-knocking down almost abolished the tumor initiation capability. Through transcriptomic analyses together with in vitro and in vivo studies, we identified insulin like growth factor 1 receptor (IGF1R) as the transcriptional target of p52-ZER6 that mediated p52-ZER6 regulation of CSC by promoting pro-survival mitophagy. Moreover, this regulation of mitophagy-mediated CSC population maintenance is specific to p52-ZER6, as p71-ZER6 failed to exert the same effect, most possibly due to the presence of the HUB1 domain at its N-terminus. These results provide a new perspective on the regulatory pathway of pro-survival mitophagy in tumor cells and the molecular mechanism underlying p52-ZER6 oncogenic activity, suggesting that targeting p52-ZER6/IGF1R axis to induce CSC pool exhaustion may be a promising anti-tumor therapeutic strategy.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: ZER6 positively regulates tumorigenesis.
Fig. 2: p52-ZER6 upregulates the expression levels of stemness markers.
Fig. 3: p52-ZER6 is crucial for CSC population maintenance.
Fig. 4: p52-ZER6 promotes CSC pro-survival mitophagy.
Fig. 5: Mitophagy is crucial for p52-ZER6 regulation on CSC population maintenance.
Fig. 6: p52-ZER6 directly regulates IGF1R transcription.
Fig. 7: IGF1R is crucial for p52-ZER6 regulation on mitophagy-mediated CSC population maintenance.
Fig. 8: p52-ZER6/IGF1R-driven CSC maintenance is crucial for tumor initiation.
Fig. 9

Similar content being viewed by others

Data availability

All data supporting the findings of this study can be freely accessed by any researcher for non-commercial purposes upon reasonable request.

References

  1. Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19:26–44.

    Article  PubMed  Google Scholar 

  2. Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, et al. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 2016;64:117–29.

    Article  CAS  PubMed  Google Scholar 

  3. Hermann PC, Bhaskar S, Cioffi M, Heeschen C. Cancer stem cells in solid tumors. Semin Cancer Biol. 2010;20:77–84.

    Article  CAS  PubMed  Google Scholar 

  4. Vasquez EG, Nasreddin N, Valbuena GN, Mulholland EJ, Belnoue-Davis HL, Eggington HR, et al. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell Stem Cell. 2022;29:1213–28.

    Article  CAS  PubMed  Google Scholar 

  5. Gao Y, Zhang Z, Li K, Gong L, Yang Q, Huang X, et al. Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells. Cell Death Dis. 2017;8:2924.

    Article  Google Scholar 

  6. Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, et al. Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma. Sci Transl Med. 2020;12:1.

    Article  Google Scholar 

  7. Duan H, Liu Y, Gao Z, Huang W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm Sin B. 2021;11:55–70.

    Article  CAS  PubMed  Google Scholar 

  8. Katajisto P, Dohla J, Chaffer CL, Pentinmikko N, Marjanovic N, Iqbal S, et al. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science. 2015;348:340–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Q, Weng K, Lin M, Jiang M, Fang Y, Chung SSW, et al. SOX9 modulates the transformation of gastric stem cells through biased symmetric cell division. Gastroenterology. 2023;1:3.

    Google Scholar 

  10. Raggi C, Taddei ML, Sacco E, Navari N, Correnti M, Piombanti B, et al. Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma. J Hepatol. 2021;74:1373–85.

    Article  CAS  PubMed  Google Scholar 

  11. Steinbichler TB, Dudas J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Therapy resistance mediated by cancer stem cells. Semin Cancer Biol. 2018;53:156–67.

    Article  CAS  PubMed  Google Scholar 

  12. Conroy AT, Sharma M, Holtz AE, Wu C, Sun Z, Weigel RJ. A novel zinc finger transcription factor with two isoforms that are differentially repressed by estrogen receptor-alpha. J Biol Chem. 2002;277:9326–34.

    Article  CAS  PubMed  Google Scholar 

  13. Stabach PR, Thiyagarajan MM, Weigel RJ. Expression of ZER6 in ERalpha-positive breast cancer. J Surg Res. 2005;126:86–91.

    Article  CAS  PubMed  Google Scholar 

  14. Huang C, Wu S, Ji H, Yan X, Xie Y, Murai S, et al. Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library. Sci Adv. 2017;3:1701383.

    Article  Google Scholar 

  15. Huang C, Wu S, Li W, Herkilini A, Miyagishi M, Zhao H, et al. Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination. EBioMedicine. 2019;48:248–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pei S, Minhajuddin M, Adane B, Khan N, Stevens BM, Mack SC, et al. AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell. 2018;23:86–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huang T, Xu T, Wang Y, Zhou Y, Yu D, Wang Z, et al. Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy. 2021;17:3592–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu K, Lee J, Kim JY, Wang L, Tian Y, Chan ST, et al. Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells. Mol Cell. 2017;68:281–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fan S, Price T, Huang W, Plue M, Warren J, Sundaramoorthy P, et al. PINK1-dependent mitophagy regulates the migration and homing of multiple myeloma cells via the MOB1B-mediated Hippo-YAP/TAZ pathway. Adv Sci. 2020;7:1900860.

    Article  CAS  Google Scholar 

  20. Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, et al. Activation mechanism of PINK1. Nature. 2022;602:328–35.

    Article  CAS  PubMed  Google Scholar 

  21. Yin K, Lee J, Liu Z, Kim H, Martin DR, Wu D, et al. Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production. Cell Death Differ. 2021;28:2421–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen Q, Lei JH, Bao J, Wang H, Hao W, Li L, et al. BRCA1 deficiency impairs mitophagy and promotes inflammasome activation and mammary tumor metastasis. Adv Sci. 2020;7:1903616.

    Article  CAS  Google Scholar 

  23. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luo J, Gong L, Yang Y, Zhang Y, Liu Q, Bai L, et al. Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in hepatocellular carcinoma. Hepatology. 2023;12:4.

    CAS  Google Scholar 

  25. You B, Xia T, Gu M, Zhang Z, Zhang Q, Shen J, et al. AMPK-mTOR-mediated activation of autophagy promotes formation of dormant polyploid giant cancer cells. Cancer Res. 2022;82:846–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yan Y, Zhang D, Zhou P, Li B, Huang SY. HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy. Nucleic Acids Res. 2017;45:365–73.

    Article  Google Scholar 

  27. Yan Y, Tao H, He J, Huang SY. The HDOCK server for integrated protein-protein docking. Nat Protoc. 2020;15:1829–52.

    Article  CAS  PubMed  Google Scholar 

  28. Ludikhuize MC, Meerlo M, Gallego MP, Xanthakis D, Burgaya Julia M, Nguyen NTB, et al. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch axis. Cell Metab. 2020;32:889–900.

    Article  CAS  PubMed  Google Scholar 

  29. Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, et al. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022;7:272.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Xu L, Liu X, Peng F, Zhang W, Zheng L, Ding Y, et al. Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions. Nat Cell Biol. 2020;22:1162–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ghaffari S. Lysosomal regulation of metabolism in quiescent hematopoietic stem cells: more than just autophagy. Cell Stem Cell. 2021;28:374–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Picard M, Shirihai OS. Mitochondrial signal transduction. Cell Metab. 2022;34:1620–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dohla J, Kuuluvainen E, Gebert N, Amaral A, Englund JI, Gopalakrishnan S, et al. Metabolic determination of cell fate through selective inheritance of mitochondria. Nat Cell Biol. 2022;24:148–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Han JX, Luo LL, Wang YC, Miyagishi M, Kasim V, Wu SR. SGLT2 inhibitor empagliflozin promotes revascularization in diabetic mouse hindlimb ischemia by inhibiting ferroptosis. Acta Pharmacol Sin. 2022;1:22.

    Google Scholar 

  35. Eldeeb MA, Thomas RA, Ragheb MA, Fallahi A, Fon EA. Mitochondrial quality control in health and in Parkinson’s disease. Physiol Rev. 2022;102:1721–55.

    Article  CAS  PubMed  Google Scholar 

  36. Wei M, Nurjanah U, Li J, Luo X, Hosea R, Li Y, et al. YY2-DRP1 axis regulates mitochondrial fission and determines cancer stem cell asymmetric division. Adv Sci. 2023;10:2207349.

    Article  CAS  Google Scholar 

  37. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12:685–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22:401–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812–24.

    Article  CAS  PubMed  Google Scholar 

  40. D’Amico D, Mottis A, Potenza F, Sorrentino V, Li H, Romani M, et al. The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol Cell. 2019;73:775–87.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wu Q, Tian AL, Li B, Leduc M, Forveille S, Hamley P, et al. IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms. J Immunother Cancer. 2021;9:7.

    Article  Google Scholar 

  42. Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson RC, Sarkaria JN, et al. Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro Oncol. 2016;18:48–57.

    Article  CAS  PubMed  Google Scholar 

  43. Stalnecker CA, Grover KR, Edwards AC, Coleman MF, Yang R, DeLiberty JM, et al. Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors. Cancer Res. 2022;82:586–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stan MN, Krieger C. Teprotumumab - a review of its adverse effects profile. J Clin Endocrinol Metab. 2023;45:77.

    Google Scholar 

  45. Dabin R, Wei C, Liang S, Ke C, Zhihan W, Ping Z. Astrocytic IGF-1 and IGF-1R orchestrate mitophagy in traumatic brain injury via exosomal miR-let-7e. Oxid Med Cell Longev. 2022;2022:3504279.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    Article  CAS  PubMed  Google Scholar 

  47. Tu Z, Karnoub AE. Mesenchymal stem/stromal cells in breast cancer development and management. Semin Cancer Biol. 2022;86:81–92.

    Article  CAS  PubMed  Google Scholar 

  48. Lin Z, Wu Y, Xu Y, Li G, Li Z, Liu T. Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Mol Cancer. 2022;21:179.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Melzer C, von der Ohe J, Lehnert H, Ungefroren H, Hass R. Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells. Mol Cancer. 2017;16:28.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Paunovska K, Loughrey D, Dahlman JE. Drug delivery systems for RNA therapeutics. Nat Rev Genet. 2022;23:265–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Miyagishi M, Taira K. Strategies for generation of an siRNA expression library directed against the human genome. Oligonucleotides. 2003;13:325–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (82372655, 82173029, 32070715 and 82203424); the Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX0611 and CSTB2022NSCQ-MSX0612).

Author information

Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Wenfang Li, Li Qiu, Yu Tang, Xia Zhang, Lei Zhang, Vivi Kasim & Shourong Wu

  2. School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi, 830017, China

    Wenfang Li

  3. Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, 230032, China

    Can Huang

  4. Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China

    Hezhao Zhao

  5. Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, 305-0006, Japan

    Makoto Miyagishi

  6. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China

    Vivi Kasim & Shourong Wu

Authors
  1. Wenfang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Can Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hezhao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makoto Miyagishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vivi Kasim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shourong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SW, VK and CH conceived and designed the project, analyzed and interpreted the experimental results, and wrote the manuscript; WL performed most of the experiments; analyzed and interpreted the experimental results, and wrote the manuscript; CH, LQ, YT, XZ, and LZ performed part of qRT-PCR and western blotting. HZ collected human clinical samples and performed clinical samples analysis. MM designed shRNA target sites and analyzed part of the data.

Corresponding authors

Correspondence to Can Huang, Vivi Kasim or Shourong Wu.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Li, W., Huang, C., Qiu, L. et al. p52-ZER6/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy. Oncogene (2024). https://doi.org/10.1038/s41388-024-03058-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-024-03058-5

Search

Advanced search

Quick links