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The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis

Oncogene volume 42, pages 2688–2700 (2023)Cite this article

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Abstract

Ferroptosis is characterized by the accumulation of lipid peroxidation as a unique iron-dependent cell death. However, the interplay between stemness and ferroptosis remains unknown. Here, we demonstrate that undifferentiated cells are more sensitive to ferroptosis than differentiated cells, and cystine transporter SLC7A11 protein is highly up-regulated by deubiquitinase DUBA in differentiated cells. Additionally, DUBA promotes stemness by deubiquitinating SLC7A11. Moreover, SLC7A11 drastically increases the expression of c-Myc through cysteine, the combination of sorafenib and c-Myc inhibitor EN4 has a synergetic effect on cancer therapy. Together, our results reveal that enhanced stemness increases the susceptibility to ferroptosis, and the DUBA-SLC7A11-c-Myc axis is pivotal for differentiated cancer stem cells (CSCs) resistant to ferroptosis, providing a promised targets to eradicate CSCs through ferroptosis.

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Fig. 1: Undifferentiated cells are more sensitive to ferroptosis than differentiated cells.
Fig. 2: SLC7A11 is up-regulated by DUBA in differentiated cells.
Fig. 3: DUBA stabilizes and interacts with SLC7A11.
Fig. 4: DUBA deubiquitinates SLC7A11.
Fig. 5: DUBA inhibits cell ferroptosis and enhances cell stemness.
Fig. 6: The DUBA-SLC7A11-c-Myc axis enhances stemness and predicts a poor prognosis in HCC Patients.
Fig. 7: The combined treatment of sorafenib and c-Myc inhibitor EN4 inhibits HCC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Bayik D, Lathia JD. Cancer stem cell-immune cell crosstalk in tumour progression. Nat Rev Cancer. 2021;21:526–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chronis C, Fiziev P, Papp B, Butz S, Bonora G, Sabri S, et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell. 2017;168:442–459.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Skamagki M, Correia C, Yeung P, Baslan T, Beck S, Zhang C, et al. Author correction: ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors. Nat Cell Biol. 2019;21:531–2.

    Article  CAS  PubMed  Google Scholar 

  4. Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633–647.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang C, Li Y, Jia L, Kim JK, Li J, Deng P, et al. CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance. Cell Stem Cell. 2021;28:1597–1613.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang Z, Chen X, Liu N, Shi Y, Liu Y, Ouyang L, et al. A nuclear long non-coding RNA LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. Mol Ther. 2021;29:263–74.

    Article  CAS  PubMed  Google Scholar 

  8. Lee J, You JH, Kim MS, Roh JL. Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer. Redox Biol. 2020;37:101697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang Y, Zhao G, Condello S, Huang H, Cardenas H, Tanner EJ, et al. Frizzled-7 identifies platinum-tolerant ovarian cancer cells susceptible to ferroptosis. Cancer Res. 2021;81:384–99.

    Article  CAS  PubMed  Google Scholar 

  10. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. El Hout M, Dos Santos L, Hamai A, Mehrpour M. A promising new approach to cancer therapy: Targeting iron metabolism in cancer stem cells. Semin Cancer Biol. 2018;53:125–38.

    Article  CAS  PubMed  Google Scholar 

  12. Zhong Q, Liu ZH, Lin ZR, Hu ZD, Yuan L, Liu YM, et al. The RARS-MAD1L1 fusion gene induces cancer stem cell-like properties and therapeutic resistance in nasopharyngeal carcinoma. Clin Cancer Res. 2018;24:659–73.

    Article  CAS  PubMed  Google Scholar 

  13. Wang M, Mao C, Ouyang L, Liu Y, Lai W, Liu N, et al. Correction to: long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ. 2020;27:1447.

    Article  PubMed  Google Scholar 

  14. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res. 2018;78:3484–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu N, Yang R, Shi Y, Chen L, Liu Y, Wang Z, et al. The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties. Signal Transduct Target Ther. 2020;5:197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hou Z, Peng H, White DE, Negorev DG, Maul GG, Feng Y, et al. LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling. Proc Natl Acad Sci USA. 2010;107:2938–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol. 2020;15:469–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stockwell BR, Jiang X, Gu W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 2020;30:478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang Z, Guo M, Li Y, Shen M, Kong D, Shao J, et al. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020;16:1482–505.

    Article  CAS  PubMed  Google Scholar 

  21. Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer FB, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169:807–823.e19.

    Article  CAS  PubMed  Google Scholar 

  22. Wang X, Chen Y, Wang X, Tian H, Wang Y, Jin J, et al. Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res. 2021;81:5217–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818–22.

    Article  CAS  PubMed  Google Scholar 

  24. Harrigan JA, Jacq X, Martin NM, Jackson SP. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2018;17:57–78.

    Article  CAS  PubMed  Google Scholar 

  25. Ouyang L, Yan B, Liu Y, Mao C, Wang M, Liu N, et al. The deubiquitylase UCHL3 maintains cancer stem-like properties by stabilizing the aryl hydrocarbon receptor. Signal Transduct Target Ther. 2020;5:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yuan L, Lv Y, Li H, Gao H, Song S, Zhang Y, et al. Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis. Nat Cell Biol. 2015;17:1169–81.

    Article  CAS  PubMed  Google Scholar 

  27. Rutz S, Kayagaki N, Phung QT, Eidenschenk C, Noubade R, Wang X, et al. Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature. 2015;518:417–21.

    Article  CAS  PubMed  Google Scholar 

  28. Chen S, Zhu JY, Zang X, Zhai YZ. The emerging role of ferroptosis in liver diseases. Front Cell Dev Biol. 2021;9:801365.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nakayama J, Gong Z. Transgenic zebrafish for modeling hepatocellular carcinoma. MedComm (2020). 2020;1:140–56.

    PubMed  Google Scholar 

  30. Klein IA, Boija A, Afeyan LK, Hawken SW, Fan M, Dall’Agnese A, et al. Partitioning of cancer therapeutics in nuclear condensates. Science. 2020;368:1386–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu W, Zhou C, Jing Q, Li Y, Yang J, Yang C, et al. FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis. Cancer Cell Int. 2021;21:709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen L, Shi Y, Liu N, Wang Z, Yang R, Yan B, et al. DNA methylation modifier LSH inhibits p53 ubiquitination and transactivates p53 to promote lipid metabolism. Epigenetics Chromatin. 2019;12:59.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Guo Y, Jiang F, Kong L, Wu H, Zhang H, Chen X, et al. OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING. Cell Mol Immunol. 2021;18:1945–55.

    Article  CAS  PubMed  Google Scholar 

  34. Huang OW, Ma X, Yin J, Flinders J, Maurer T, Kayagaki N, et al. Phosphorylation-dependent activity of the deubiquitinase DUBA. Nat Struct Mol Biol. 2012;19:171–5.

    Article  CAS  PubMed  Google Scholar 

  35. Das B, Pal B, Bhuyan R, Li H, Sarma A, Gayan S, et al. MYC regulates the HIF2alpha stemness pathway via Nanog and Sox2 to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer Res. 2019;79:4015–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020;368:85–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75:1782–8.

    Article  CAS  PubMed  Google Scholar 

  38. Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, et al. Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab. 2020;31:892–908.e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yuan H, Han Y, Wang X, Li N, Liu Q, Yin Y, et al. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell. 2020;38:350–65.e7.

    Article  CAS  PubMed  Google Scholar 

  40. Gao R, Kalathur RKR, Coto-Llerena M, Ercan C, Buechel D, Shuang S, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13:e14351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Boike L, Cioffi AG, Majewski FC, Co J, Henning NJ, Jones MD, et al. Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chem Biol. 2021;28:4–13.e17.

    Article  CAS  PubMed  Google Scholar 

  42. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Saba JA, Liakath-Ali K, Green R, Watt FM. Translational control of stem cell function. Nat Rev Mol Cell Biol. 2021;22:671–90.

    Article  CAS  PubMed  Google Scholar 

  44. Dong Z, Zhang G, Qu M, Gimple RC, Wu Q, Qiu Z, et al. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 2019;9:1556–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park SY, Kim JY, Choi JH, Kim JH, Lee CJ, Singh P, et al. Inhibition of LEF1-mediated DCLK1 by niclosamide attenuates colorectal cancer stemness. Clin Cancer Res. 2019;25:1415–29.

    Article  CAS  PubMed  Google Scholar 

  46. Dong S, Wang Q, Kao YR, Diaz A, Tasset I, Kaushik S, et al. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature. 2021;591:117–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu Y, Zhang Y, Garcia-Canaveras JC, Guo L, Kan M, Yu S, et al. Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells. Science. 2020;369:397–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L. Emerging agents that target signaling pathways in cancer stem cells. J Hematol Oncol. 2020;13:60.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 2019;9:1673–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu T, Jiang L, Tavana O, Gu W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 2019;79:1913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dinallo V, Di Fusco D, Di Grazia A, Laudisi F, Troncone E, Di G. et al. The deubiquitinating enzyme OTUD5 sustains inflammatory cytokine response in inflammatory bowel disease. J Crohns Colitis. 2022;16:122–32.

    Article  PubMed  Google Scholar 

  52. Do EK, Moon HJ, Kang KT, Yoon JW, Kim YS, Seo JK, et al. Kap1 regulates the self-renewal of embryonic stem cells and cellular reprogramming by modulating Oct4 protein stability. Cell Death Differ. 2021;28:685–99.

    Article  CAS  PubMed  Google Scholar 

  53. Cui CP, Zhang Y, Wang C, Yuan F, Li H, Yao Y, et al. Author correction: dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation. Nat Commun. 2019;10:173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang J, Zhang Y, Hou J, Qian X, Zhang H, Zhang Z, et al. Ube2s regulates Sox2 stability and mouse ES cell maintenance. Cell Death Differ. 2016;23:393–404.

    Article  CAS  PubMed  Google Scholar 

  55. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019;572:402–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12:599–620.

    Article  CAS  PubMed  Google Scholar 

  57. Liu Y, Ouyang L, Mao C, Chen Y, Li T, Liu N, et al. PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma. Oncogene. 2022;41:3570–83.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Xiaoying Wu and Jin Lin at the Central South University for technical assistance with Transmission electron microscopy. We appreciate Lingqiang Zhang at Peking University for assistance with 89 DUB plasmids. We thank all the members of the laboratory for their resourceful comments on the manuscript. This work was supported by the National Natural Science Foundation of China [82072594, YT; 82073097, 81874139 SL; 82073136, 81772927, DX; 82002916, CM], China Postdoctoral Science Foundation [2019M652804, CM], Natural Science Foundation of Hunan Province [2020JJ5790, CM], Hunan Provincial Key Area R&D Programs [2021SK2013, YT], Young Project of Universities Scientific Research in Guizhou Provincial Education Department [QianJiaoJi(2022)185, ZW], Scientific Research Start Foundation of high level talents in Guizhou Medical University [XiaoBoHe-J-(2022)037, ZW].

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Authors and Affiliations

  1. Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou, 550025, China

    Zuli Wang

  2. Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China

    Zuli Wang, Lianlian Ouyang, Na Liu, Tiansheng Li, Bokang Yan, Chao Mao & Yongguang Tao

  3. NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China

    Zuli Wang, Lianlian Ouyang, Na Liu, Tiansheng Li, Bokang Yan, Chao Mao & Yongguang Tao

  4. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Desheng Xiao & Yongguang Tao

  5. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Boyi Gan

  6. Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Shuang Liu

  7. Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Yongguang Tao

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Contributions

In this study, YT and ZW designed the experimental scheme and drafted the manuscript. ZW performed the experiments and data analysis. NL and LO assisted with stemness-related experiments. BY and TL help with preparation for experimental materials. SL provided help for FACS and DX provided help for IHC and modified the original paper. The paper was approved by all authors.

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Correspondence to Shuang Liu or Yongguang Tao.

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Wang, Z., Ouyang, L., Liu, N. et al. The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis. Oncogene 42, 2688–2700 (2023). https://doi.org/10.1038/s41388-023-02744-0

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