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M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

Oncogene volume 41, pages 1727–1741 (2022)Cite this article

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Abstract

Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening showed that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson’s disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has preclinical value to be repurposed for OS.

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Fig. 1: Identification of FTO as a candidate therapeutic target that is upregulated in OS.
Fig. 2: FTO is required for OS growth and metastasis in vitro and in vivo.
Fig. 3: Identification of m6A modification targets and DACT1 as an essential target of FTO.
Fig. 4: DACT1 acts as a tumor suppressor in OS and its downregulation mediates the oncogenic effect of FTO in vitro.
Fig. 5: Loss of DACT1 reverses the suppression of OS caused by FTO inhibition in vivo.
Fig. 6: Correlation between and clinical relevance of FTO and DACT1 in OS tissues.
Fig. 7: The FTO inhibitor entacapone has potential as an anti-osteosarcoma agent.
Fig. 8: A proposed model of the biological function of FTO in OS.

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Data availability

The RNA-seq and MeRIP-seq data in this study have been deposited in the GEO database under the accession code: GSE189880.

References

  1. Simpson E, Brown HL. Understanding osteosarcomas. JAAPA. 2018;31:15–9.

    Article  PubMed  Google Scholar 

  2. Yang C, Tian Y, Zhao F, Chen Z, Su P, Li Y, et al. Bone microenvironment and osteosarcoma metastasis. Int J Mol Sci. 2020;21:6985.

    Article  PubMed Central  Google Scholar 

  3. Eaton BR, Schwarz R, Vatner R, Yeh B, Claude L, Indelicato DJ, et al. Osteosarcoma. Pediatr Blood Cancer. 2020, e28352. https://doi.org/10.1002/pbc.28352.

  4. Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.

    Article  Google Scholar 

  5. Harrison DJ, Geller DS, Gill JD, Lewis VO, Gorlick R. Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther. 2018;18:39–50.

    Article  CAS  PubMed  Google Scholar 

  6. Lv D, Zou Y, Zeng Z, Yao H, Ding S, Bian Y, et al. Comprehensive metabolomic profiling of osteosarcoma based on UHPLC-HRMS. Metabolomics.2020;16:120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42.

    Article  CAS  PubMed  Google Scholar 

  8. Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20:303–22.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou Z, Lv J, Yu H, Han J, Yang X, Feng D, et al. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol Cancer. 2020;19:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen Y, Wang J, Xu D, Xiang Z, Ding J, Yang X, et al. m(6)A mRNA methylation regulates testosterone synthesis through modulating autophagy in Leydig cells. Autophagy. 2020;17:1–19.

    Google Scholar 

  11. Berulava T, Buchholz E, Elerdashvili V, Pena T, Islam MR, Lbik D, et al. Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail. 2020;22:54–66.

    Article  CAS  PubMed  Google Scholar 

  12. Zhou B, Liu C, Xu L, Yuan Y, Zhao J, Zhao W, et al. N(6) -Methyladenosine reader protein YT521-B homology domain-containing 2 suppresses liver steatosis by regulation of mRNA stability of lipogenic genes. Hepatology.2021;73:91–103.

    Article  CAS  PubMed  Google Scholar 

  13. Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, et al. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 2020;19:106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lin Z, Niu Y, Wan A, Chen D, Liang H, Chen X, et al. RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J. 2020;39:e103181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen H, Gao S, Liu W, Wong CC, Wu J, Wu J, et al. RNA N(6)-methyladenosine methyltransferase METTL3 facilitates colorectal cancer by activating the m(6)A-GLUT1-mTORC1 axis and is a therapeutic target. Gastroenterology.2021;160:1284–1300.

    Article  CAS  PubMed  Google Scholar 

  16. Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37:270–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science.2007;316:889–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, et al. Inactivation of the Fto gene protects from obesity. Nature.2009;458:894–8.

    Article  CAS  PubMed  Google Scholar 

  20. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-Methyladenosine RNA Demethylase. Cancer Cell. 2017;31:127–41.

    Article  PubMed  Google Scholar 

  21. Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L, et al. RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 2019;18:46.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhuang C, Zhuang C, Luo X, Huang X, Yao L, Li J, et al. N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1alpha signalling axis. J Cell Mol Med. 2019;23:2163–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gilbert WV, Bell TA, Schaening C. Messenger RNA modifications: form, distribution, and function. Science.2016;352:1408–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lan T, Li H, Zhang D, Xu L, Liu H, Hao X, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol Cancer. 2019;18:186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yin X, Xiang T, Li L, Su X, Shu X, Luo X, et al. DACT1, an antagonist to Wnt/beta-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer. Breast Cancer Res. 2013;15:R23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang JH, Lin LK, Zhang S. Effects of DACT1 methylation status on invasion and metastasis of nasopharyngeal carcinoma. Biol Res. 2019;52:31.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell.2015;161:1388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, et al. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507–19.

    Article  CAS  PubMed  Google Scholar 

  29. Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang L, Gao X, Wen J, Ning Y, Chen YG. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem. 2006;281:8607–12.

    Article  CAS  PubMed  Google Scholar 

  31. Gao X, Wen J, Zhang L, Li X, Ning Y, Meng A, et al. Dapper1 is a nucleocytoplasmic shuttling protein that negatively modulates Wnt signaling in the nucleus. J Biol Chem. 2008;283:35679–88.

    Article  CAS  PubMed  Google Scholar 

  32. Peng S, Xiao W, Ju D, Sun B, Hou N, Liu Q, et al. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med. 2019;11:eaau7116.

    Article  PubMed  Google Scholar 

  33. Cacabelos R. Parkinson’s disease: from pathogenesis to pharmacogenomics. Int J Mol Sci. 2017;18:551.

    Article  PubMed Central  Google Scholar 

  34. Gordin A, Kaakkola S, Teravainen H. Clinical advantages of COMT inhibition with entacapone - a review. J Neural Transm (Vienna). 2004;111:1343–63.

    Article  CAS  Google Scholar 

  35. Sun T, Wu Z, Wang X, Wang Y, Hu X, Qin W, et al. LNC942 promoting METTL14-mediated m(6)A methylation in breast cancer cell proliferation and progression. Oncogene.2020;39:5358–72.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene.2020;39:4507–18.

    Article  CAS  PubMed  Google Scholar 

  37. Chen S, Li Y, Zhi S, Ding Z, Wang W, Peng Y, et al. WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m(6)A-dependent manner. Cell Death Dis. 2020;11:659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou L, Yang C, Zhang N, Zhang X, Zhao T, Yu J. Silencing METTL3 inhibits the proliferation and invasion of osteosarcoma by regulating ATAD2. Biomed Pharmacother. 2020;125:109964.

    Article  CAS  PubMed  Google Scholar 

  39. Wang Y, Zeng L, Liang C, Zan R, Ji W, Zhang Z, et al. Integrated analysis of transcriptome-wide m(6)A methylome of osteosarcoma stem cells enriched by chemotherapy. Epigenomics.2019;11:1693–715.

    Article  CAS  PubMed  Google Scholar 

  40. Li J, Rao B, Yang J, Liu L, Huang M, Liu X, et al. Dysregulated m6A-related regulators are associated with tumor metastasis and poor prognosis in osteosarcoma. Front Oncol. 2020;10:769.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liu H, Qin G, Ji Y, Wang X, Bao H, Guan X, et al. Potential role of m6A RNA methylation regulators in osteosarcoma and its clinical prognostic value. J Orthop Surg Res. 2021;16:294.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yang S, Wei J, Cui YH, Park G, Shah P, Deng Y, et al. m(6)A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019;10:2782.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Xiao Y, Thakkar KN, Zhao H, Broughton J, Li Y, Seoane JA, et al. The m(6)A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor. Proc Natl Acad Sci USA. 2020;117:21441–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fisher DA, Kivimae S, Hoshino J, Suriben R, Martin PM, Baxter N, et al. Three Dact gene family members are expressed during embryonic development and in the adult brains of mice. Dev Dyn. 2006;235:2620–30.

    Article  CAS  PubMed  Google Scholar 

  46. Okerlund ND, Kivimae S, Tong CK, Peng IF, Ullian EM, Cheyette BN. Dact1 is a postsynaptic protein required for dendrite, spine, and excitatory synapse development in the mouse forebrain. J Neurosci. 2010;30:4362–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Esposito M, Fang C, Cook KC, Park N, Wei Y, Spadazzi C, et al. TGF-beta-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nat Cell Biol. 2021;23:257–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matsuoka K, Bakiri L, Wolff LI, Linder M, Mikels-Vigdal A, Patino-Garcia A, et al. Wnt signaling and Loxl2 promote aggressive osteosarcoma. Cell Res. 2020;30:885–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu S, Liu Y, Wang X, Wang J, Xi G. lncRNA SNHG10 promotes the proliferation and invasion of osteosarcoma via Wnt/beta-catenin signaling. Mol Ther Nucleic Acids. 2020;22:957–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35:677–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Su R, Dong L, Li Y, Gao M, Han L, Wunderlich M, et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell. 2020;38:79–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liao D, Zhong L, Duan T, Zhang RH, Wang X, Wang G, et al. Aspirin suppresses the growth and metastasis of osteosarcoma through the NF-kappaB pathway. Clin Cancer Res. 2015;21:5349–59.

    Article  CAS  PubMed  Google Scholar 

  53. Stojic L, Lun ATL, Mascalchi P, Ernst C, Redmond AM, Mangei J, et al. A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division. Nat Commun. 2020;11:1851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhong L, Liao D, Li J, Liu W, Wang J, Zeng C, et al. Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes. Signal Transduct Target Ther. 2021;6:59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li H, Tu J, Zhao Z, Chen L, Qu Y, Li H, et al. Molecular signatures of BRCAness analysis identifies PARP inhibitor Niraparib as a novel targeted therapeutic strategy for soft tissue Sarcomas. Theranostics.2020;10:9477–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252–61.

    Article  CAS  PubMed  Google Scholar 

  57. Chen CY, Ezzeddine N, Shyu AB. Messenger RNA half-life measurements in mammalian cells. Methods Enzymol. 2008;448:335–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang X, Qin G, Liang X, Wang W, Wang Z, Liao D, et al. Targeting the CK1alpha/CBX4 axis for metastasis in osteosarcoma. Nat Commun. 2020;11:1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by National Natural Science Foundation of China (Grants 81972510, 81772864 and 81572638), Natural Science Foundation of Guangdong Province (No.2016A030313239), and Medical Scientific Research Foundation of Guangdong Province (A2020483).

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Author notes

  1. These authors contributed equally: Dongming Lv, Shirong Ding.

Authors and Affiliations

  1. Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Dongming Lv, Jian Tu, Hongbo Li, Hao Yao, Yutong Zou, Ziliang Zeng, Yan Liao & Xianbiao Xie

  2. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China

    Dongming Lv, Jian Tu, Hongbo Li, Hao Yao, Yutong Zou, Ziliang Zeng, Yan Liao & Xianbiao Xie

  3. Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, China

    Shirong Ding

  4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Li Zhong

  5. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

    Li Zhong

  6. Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Xuesi Wan

  7. Department of Anesthesiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Lili Wen

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Contributions

XX and LW conceived of, designed, and supervised the study; DL, SD, LZ, JT, and HL performed the experiments and analyzed the data; DL, HY, YZ, ZZ, YL, and XW provided technical assistance with the experiments; DL wrote the manuscript. All co-authors have reviewed and approved this version of the manuscript.

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Correspondence to Lili Wen or Xianbiao Xie.

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Lv, D., Ding, S., Zhong, L. et al. M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression. Oncogene 41, 1727–1741 (2022). https://doi.org/10.1038/s41388-022-02214-z

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