The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Autoři: Elizabeth A. Coe aff001;  Jennifer Y. Tan aff002;  Michael Shapiro aff001;  Pakavarin Louphrasitthiphol aff003;  Andrew R. Bassett aff004;  Ana C. Marques aff002;  Colin R. Goding aff003;  Keith W. Vance aff001
Působiště autorů: Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom aff001;  Department of Computational Biology, University of Lausanne, Lausanne, Switzerland aff002;  Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom aff003;  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom aff004
Vyšlo v časopise: The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008501
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008501


The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. Our work suggests that one of these, Disrupted In Renal Carcinoma 3 (DIRC3), may be a clinically important MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that activates expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in cancer associated processes and is needed for DIRC3 control of anchorage-independent growth. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets that can act not only as downstream mediators of MITF-SOX10 function but as feedback regulators of MITF-SOX10 activity.

Klíčová slova:

Gene expression – Gene regulation – Chromatin – Long non-coding RNAs – Melanoma cells – Melanomas – Transcriptional control – Tumor suppressor genes


1. Kopp F, Mendell JT. Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell. 2018;172(3):393–407. doi: 10.1016/j.cell.2018.01.011 29373828.

2. Vance KW, Ponting CP. Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet. 2014;30(8):348–55. doi: 10.1016/j.tig.2014.06.001 24974018.

3. Blank-Giwojna A, Postepska-Igielska A, Grummt I. lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators. Cell reports. 2019;26(11):2904–15.e4. doi: 10.1016/j.celrep.2019.02.059 30865882.

4. Davidovich C, Goodrich KJ, Gooding AR, Cech TR. A dimeric state for PRC2. Nucleic Acids Res. 2014;42(14):9236–48. doi: 10.1093/nar/gku540 24992961.

5. Anderson KM, Anderson DM, McAnally JR, Shelton JM, Bassel-Duby R, Olson EN. Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature. 2016;539(7629):433–6. doi: 10.1038/nature20128 27783597.

6. Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature. 2016;539(7629):452–5. doi: 10.1038/nature20149 27783602.

7. Chalei V, Sansom SN, Kong L, Lee S, Montiel JF, Vance KW, et al. The long non-coding RNA is an epigenetic regulator of neural differentiation. eLife. 2014;3. doi: 10.7554/eLife.04530 25415054.

8. Pavlaki I, Alammari F, Sun B, Clark N, Sirey T, Lee S, et al. The long non-coding RNA Paupar promotes KAP1-dependent chromatin changes and regulates olfactory bulb neurogenesis. The EMBO journal. 2018;37:e98219. doi: 10.15252/embj.201798219 29661885.

9. Vance KW, Sansom SN, Lee S, Chalei V, Kong L, Cooper SE, et al. The long non-coding RNA Paupar regulates the expression of both local and distal genes. The EMBO journal. 2014;33(4):296–311. doi: 10.1002/embj.201386225 24488179.

10. Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, et al. Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers. Cancer cell. 2015;28(4):529–40. doi: 10.1016/j.ccell.2015.09.006 26461095.

11. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nature genetics. 2015;47(3):199–208. doi: 10.1038/ng.3192 25599403.

12. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142(3):409–19. doi: 10.1016/j.cell.2010.06.040 20673990.

13. Marin-Bejar O, Mas AM, Gonzalez J, Martinez D, Athie A, Morales X, et al. The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element. Genome Biol. 2017;18(1):202. doi: 10.1186/s13059-017-1331-y 29078818.

14. Hart JR, Roberts TC, Weinberg MS, Morris KV, Vogt PK. MYC regulates the non-coding transcriptome. Oncotarget. 2014;5(24):12543–54. doi: 10.18632/oncotarget.3033 25587025.

15. Kim T, Jeon YJ, Cui R, Lee JH, Peng Y, Kim SH, et al. Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis. J Natl Cancer Inst. 2015;107(4). doi: 10.1093/jnci/dju505 25663692.

16. Flockhart RJ, Webster DE, Qu K, Mascarenhas N, Kovalski J, Kretz M, et al. BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration. Genome research. 2012;22(6):1006–14. doi: 10.1101/gr.140061.112 22581800.

17. Montes M, Nielsen MM, Maglieri G, Jacobsen A, Hojfeldt J, Agrawal-Singh S, et al. The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nature communications. 2015;6:6967. doi: 10.1038/ncomms7967 25908244.

18. Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, et al. Melanoma addiction to the long non-coding RNA SAMMSON. Nature. 2016;531(7595):518–22. doi: 10.1038/nature17161 27008969.

19. Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek KS, et al. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes & development. 2006;20(24):3426–39. doi: 10.1101/gad.406406 17182868.

20. Goding CR, Arnheiter H. MITF-the first 25 years. Genes & development. 2019;33(15–16):983–1007. Epub 2019/05/28. doi: 10.1101/gad.324657.119 31123060.

21. Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer cell. 2013;23(3):302–15. doi: 10.1016/j.ccr.2013.02.003 23477830.

22. Louphrasitthiphol P, Ledaki I, Chauhan J, Falletta P, Siddaway R, Buffa FM, et al. MITF controls the TCA cycle to modulate the melanoma hypoxia response. Pigment cell & melanoma research. 2019. Epub 2019/06/18. doi: 10.1111/pcmr.12802 31207090.

23. Strub T, Giuliano S, Ye T, Bonet C, Keime C, Kobi D, et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene. 2011;30(20):2319–32. doi: 10.1038/onc.2010.612 21258399.

24. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436(7047):117–22. doi: 10.1038/nature03664 16001072.

25. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000;9(13):1907–17. Epub 2000/08/15. doi: 10.1093/hmg/9.13.1907 10942418.

26. Lee M, Goodall J, Verastegui C, Ballotti R, Goding CR. Direct regulation of the Microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS2. J Biol Chem. 2000;275(48):37978–83. Epub 2000/09/07. doi: 10.1074/jbc.M003816200 10973953.

27. Potterf SB, Furumura M, Dunn KJ, Arnheiter H, Pavan WJ. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Hum Genet. 2000;107(1):1–6. Epub 2000/09/12. doi: 10.1007/s004390000328 10982026.

28. Verastegui C, Bille K, Ortonne JP, Ballotti R. Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. J Biol Chem. 2000;275(40):30757–60. Epub 2000/08/12. doi: 10.1074/jbc.C000445200 10938265.

29. Laurette P, Strub T, Koludrovic D, Keime C, Le Gras S, Seberg H, et al. Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells. eLife. 2015;4. doi: 10.7554/eLife.06857 25803486.

30. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508(7494):118–22. doi: 10.1038/nature13121 24670642.

31. Verfaillie A, Imrichova H, Atak ZK, Dewaele M, Rambow F, Hulselmans G, et al. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nature communications. 2015;6:6683. doi: 10.1038/ncomms7683 25865119.

32. Fiziev P, Akdemir KC, Miller JP, Keung EZ, Samant NS, Sharma S, et al. Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression. Cell reports. 2017;19(4):875–89. doi: 10.1016/j.celrep.2017.03.078 28445736.

33. Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. Peerj Comput Sci. 2016;2:e67. ARTN e67 doi: 10.7717/peerj-cs.67

34. Hall EH, Daugherty AE, Choi CK, Horwitz AF, Brautigan DL. Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. J Biol Chem. 2009;284(50):34713–22. doi: 10.1074/jbc.M109.059592 19826001.

35. Wang J, Ding N, Li Y, Cheng H, Wang D, Yang Q, et al. Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells. Oncotarget. 2015;6(24):20636–49. doi: 10.18632/oncotarget.4114 26010068.

36. Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159(7):1665–80. doi: 10.1016/j.cell.2014.11.021 25497547.

37. Sauerwald N, Kingsford C. Quantifying the similarity of topological domains across normal and cancer human cell types. Bioinformatics. 2018;34(13):i475–i83. Epub 2018/06/29. doi: 10.1093/bioinformatics/bty265 29949963.

38. Ntini E, Louloupi A, Liz J, Muino JM, Marsico A, Orom UAV. Long ncRNA A-ROD activates its target gene DKK1 at its release from chromatin. Nature communications. 2018;9(1):1636. Epub 2018/04/25. doi: 10.1038/s41467-018-04100-3 29691407.

39. Mori S, Chang JT, Andrechek ER, Matsumura N, Baba T, Yao G, et al. Anchorage-independent cell growth signature identifies tumors with metastatic potential. Oncogene. 2009;28(31):2796–805. doi: 10.1038/onc.2009.139 19483725.

40. Clemmons DR. Role of IGF Binding Proteins in Regulating Metabolism. Trends Endocrinol Metab. 2016;27(6):375–91. doi: 10.1016/j.tem.2016.03.019 27117513.

41. Tripathi G, Salih DA, Drozd AC, Cosgrove RA, Cobb LJ, Pell JM. IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo. FASEB J. 2009;23(8):2616–26. doi: 10.1096/fj.08-114124 19332648.

42. Dryden NH, Broome LR, Dudbridge F, Johnson N, Orr N, Schoenfelder S, et al. Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C. Genome research. 2014;24(11):1854–68. Epub 2014/08/15. doi: 10.1101/gr.175034.114 25122612.

43. Wyszynski A, Hong CC, Lam K, Michailidou K, Lytle C, Yao S, et al. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Hum Mol Genet. 2016;25(17):3863–76. doi: 10.1093/hmg/ddw223 27402876.

44. Maitituoheti M, Keung Emily, Tang Ming, Yan Liang, Alam Hunain, Han Guangchan, et al. Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma. BioRxiv.Preprint.

45. Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L, et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer research. 2008;68(3):650–6. doi: 10.1158/0008-5472.CAN-07-2491 18245463.

46. Falletta P, Sanchez-Del-Campo L, Chauhan J, Effern M, Kenyon A, Kershaw CJ, et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes & development. 2017;31(1):18–33. doi: 10.1101/gad.290940.116 28096186.

47. Ferguson J, Smith M, Zudaire I, Wellbrock C, Arozarena I. Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth. Oncotarget. 2017;8(20):32946–59. Epub 2017/04/06. doi: 10.18632/oncotarget.16514 28380427.

48. Garcia-Jimenez C, Goding CR. Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming. Cell Metab. 2019;29(2):254–67. Epub 2018/12/26. doi: 10.1016/j.cmet.2018.11.018 30581118.

49. Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH, et al. Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation. Cell. 2014;159(3):647–61. doi: 10.1016/j.cell.2014.09.029 25307932.

50. Ilott NE, Ponting CP. Predicting long non-coding RNAs using RNA sequencing. Methods. 2013;63(1):50–9. doi: 10.1016/j.ymeth.2013.03.019 23541739.

51. Sims D, Ilott NE, Sansom SN, Sudbery IM, Johnson JS, Fawcett KA, et al. CGAT: computational genomics analysis toolkit. Bioinformatics. 2014;30(9):1290–1. doi: 10.1093/bioinformatics/btt756 24395753.

52. Riesenberg S, Groetchen A, Siddaway R, Bald T, Reinhardt J, Smorra D, et al. MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment. Nature communications. 2015;6:8755. doi: 10.1038/ncomms9755 26530832.

53. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. doi: 10.1093/bioinformatics/btu638 25260700.

54. Durand NC, Robinson JT, Shamim MS, Machol I, Mesirov JP, Lander ES, et al. Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom. Cell Syst. 2016;3(1):99–101. doi: 10.1016/j.cels.2015.07.012 27467250.

Genetika Reprodukční medicína

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PLOS Genetics

2019 Číslo 12

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