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MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis

Oncogene volume 41, pages 560–570 (2022)Cite this article

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Abstract

Melanoma is a type of skin cancer that develops in pigment-producing melanocytes and often spreads to other parts of the body. Aberrant gene expression has been considered as a crucial step for increasing the risk of melanomagenesis, but how chromatin reorganization contributes to this pathogenic process is still not well understood. Here we report that matrix metalloproteinase 9 (MMP-9) localizes to the nucleus of melanoma cells and potentiates gene expression by proteolytically clipping the histone H3 N-terminal tail (H3NT). From genome-wide studies, we discovered that growth-regulatory genes are selectively targeted and activated by MMP-9-dependent H3NT proteolysis in melanoma cells. MMP-9 cooperates functionally with p300/CBP because MMP-9 cleaves H3NT in a manner that is dependent on p300/CBP-mediated acetylation of H3K18. The functional significance of MMP-9-dependent H3NT proteolysis is further underscored by the fact that RNAi knockdown and small-molecule inhibition of MMP-9 and p300/CBP impede melanomagenic gene expression and melanoma tumor growth. Together, our data establish new functions and mechanisms for nuclear MMP-9 in promoting melanomagenesis and demonstrate how MMP-9-dependent H3NT proteolysis can be exploited to prevent and treat melanoma skin cancer.

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Fig. 1: High levels of MMP-9 expression and H3NT proteolysis in melanoma cells.
Fig. 2: MMP-9-dependent H3NT proteolysis in melanoma cells.
Fig. 3: Regulation of melanogenic genes by MMP-9.
Fig. 4: MMP-9 localization and function at melanogenic genes.
Fig. 5: Effects of MMP-9 knockdown and inhibition on melanoma cell growth in vitro.
Fig. 6: Effects of MMP-9 knockdown on melanoma tumor growth in vivo.
Fig. 7: Effects of MMP-9 inhibition on melanoma tumor growth in vivo.

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References

  1. Boissy RE, Nordlund JJ. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res. 1997;10:12–24.

    Article  CAS  PubMed  Google Scholar 

  2. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nat. 2007;445:851–7.

    Article  CAS  Google Scholar 

  3. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiological Rev. 2004;84:1155–228.

    Article  CAS  Google Scholar 

  4. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  Google Scholar 

  5. Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003;63:3883–5.

    CAS  PubMed  Google Scholar 

  6. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66:9483–91.

    Article  CAS  PubMed  Google Scholar 

  7. Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47:996–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen H, Weng QY, Fisher DE. UV signaling pathways within the skin. J Investig Dermatol. 2014;134:2080–5.

    Article  CAS  PubMed  Google Scholar 

  9. Fu C, Chen J, Lu J, Yi L, Tong X, Kang L, et al. Roles of inflammation factors in melanogenesis (Review). Mol Med Rep. 2020;21:1421–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Körner A, Pawelek J. Mammalian tyrosinase catalyzes three reactions in the biosynthesis of melanin. Science. 1982;217:1163–5.

    Article  PubMed  Google Scholar 

  11. Zhou S, Zeng H, Huang J, Lei L, Tong X, Li S, et al. Epigenetic regulation of melanogenesis. Ageing Res Rev. 2021;69:101349.

    Article  CAS  PubMed  Google Scholar 

  12. Hoffmann F, Niebel D, Aymans P, Ferring-Schmitt S, Dietrich D. Landsberg J. H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade. Clin Epigenet. 2020;12:24.

    Article  CAS  Google Scholar 

  13. Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ. Role of EZH2 histone methyltrasferase in melanoma progression and metastasis. Cancer Biol Ther. 2016;17:579–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Faião-Flores F, Emmons MF, Durante MA, Kinose F, Saha B, Fang B, et al. HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma. Clin Cancer Res. 2019;25:5686–701.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wilmott JS, Colebatch AJ, Kakavand H, Shang P, Carlino MS, Thompson JF, et al. Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma. Mod Pathol. 2015;28:884–94.

    Article  CAS  PubMed  Google Scholar 

  16. Lue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A, Mundi PS, et al. Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas. Clin Cancer Res. 2019;25:5271–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell. 2012;22:506–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Agrawal A, Romero-Perez D, Jacobsen JA, Villarreal FJ, Cohen SM. Zinc-binding groups modulate selective inhibition of MMPs. ChemMedChem. 2008;3:812–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bruschi F, Pinto B. The significance of matrix metalloproteinases in parasitic infections involving the central nervous system. Pathogens. 2013;2:105–29.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 2011;41:271–90.

    Article  CAS  PubMed  Google Scholar 

  21. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73.

    Article  CAS  PubMed  Google Scholar 

  22. Santos MC, de Souza AP, Gerlach RF, Trevilatto PC, Scarel-Caminaga RM, Line SR. Inhibition of human pulpal gelatinases (MMP-2 and MMP-9) by zinc oxide cements. J Oral Rehabil. 2004;31:660–4.

    Article  CAS  PubMed  Google Scholar 

  23. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol. 2002;37:375–536.

    Article  PubMed  Google Scholar 

  24. Vandooren J, Van den Steen PE, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol. 2013;48:222–72.

    Article  CAS  Google Scholar 

  25. Kim K, Shin Y, Kim J, Ulmer TS, An W. H3K27me1 is essential for MMP-9-dependent H3N-terminal tail proteolysis during osteoclastogenesis. Epigenetics Chromatin. 2018;11:23.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Papazafiropoulou A, Tentolouris N. Matrix metalloproteinases and cardiovascular diseases. Hippokratia. 2009;13:76–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2:737–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995;7:728–35.

    Article  CAS  PubMed  Google Scholar 

  29. Vargová V, Pytliak M, Mechírová V. Matrix metalloproteinases. Experientia Supplementum (2012). 2012;103:1–33.

    Article  Google Scholar 

  30. Kim K, Punj V, Kim JM, Lee S, Ulmer TS, Lu W, et al. MMP-9 facilitates selective proteolysis of the histone H3 tail at genes necessary for proficient osteoclastogenesis. Genes Dev. 2016;30:208–19.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shin Y, Ghate NB, Moon B, Park K, Lu W, An W. DNMT and HDAC inhibitors modulate MMP-9-dependent H3 N-terminal tail proteolysis and osteoclastogenesis. Epigenetics Chromatin. 2019;12:25.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Guarneri C, Bevelacqua V, Polesel J, Falzone L, Cannavò PS, Spandidos DA, et al. NF‑κB inhibition is associated with OPN/MMP‑9 downregulation in cutaneous melanoma. Oncol Rep. 2017;37:737–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Napoli S, Scuderi C, Gattuso G, Bella VD, Candido S, Basile MS, et al. Functional roles of matrix metalloproteinases and their inhibitors in melanoma. Cells. 2020;9:1151.

    Article  PubMed Central  Google Scholar 

  34. Rangaswami H, Kundu GC. Osteopontin stimulates melanoma growth and lung metastasis through NIK/MEKK1-dependent MMP-9 activation pathways. Oncol Rep. 2007;18:909–15.

    CAS  PubMed  Google Scholar 

  35. Ding L, Wen Y, Zhang X, Zhao F, Lv K, Shi J-H, et al. Transcriptional network constituted of CBP, Ku70, NOX2, and BAX prevents the cell death of necrosis, paraptosis, and apoptosis in human melanoma. Cell Death Discov. 2021;7:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lin WM, Baker AC, Beroukhim R, Winckler W, Feng W, Marmion JM, et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 2008;68:664–73.

    Article  CAS  PubMed  Google Scholar 

  37. Rice JC, Weekley BH, Kanholm T, Chen Z, Lee S, Fernandez DJ, et al. MMP-2 is a novel histone H3 N-terminal protease necessary for myogenic gene activation. Epigenetics Chromatin. 2021;14:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Daura E, Tegelberg S, Yoshihara M, Jackson C, Simonetti F, Aksentjeff K, et al. Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis. Neurobiol Dis. 2021;156:105418.

    Article  CAS  PubMed  Google Scholar 

  39. Ferrari KJ, Amato S, Noberini R, Toscani C, Fernández-Pérez D, Rossi A, et al. Intestinal differentiation involves cleavage of histone H3 N-terminal tails by multiple proteases. Nucleic Acids Res. 2021;49:791–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen J, Xiang X, Chen L, Wang H, Wu L, Sun Y, et al. JMJD5 cleaves monomethylated histone H3 N-tail under DNA damaging stress. EMBO Rep. 2017;18:2131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim E, Zucconi BE, Wu M, Nocco SE, Meyers DJ, McGee JS, et al. MITF expression predicts therapeutic vulnerability to p300 inhibition in human melanoma. Cancer Res. 2019;79:2649–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang R, He Y, Robinson V, Yang Z, Hessler P, Lasko LM, et al. Targeting lineage-specific MITF pathway in human melanoma cell lines by A-485, the selective small-molecule inhibitor of p300/CBP. Mol Cancer Therapeutics. 2018;17:2543–50.

    Article  CAS  Google Scholar 

  43. Kim JM, Shin Y, Lee S, Kim MY, Punj V, Shin HI, et al. MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2. Oncogene. 2018;37:5749–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Frankish A, Diekhans M, Ferreira A-M, Johnson R, Jungreis I, Loveland J, et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 2019;47:D766–D773.

    Article  CAS  PubMed  Google Scholar 

  45. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  Google Scholar 

  46. Bähler J, Zhao X, Valen E, Parker BJ, Sandelin A. Systematic clustering of transcription start site landscapes. PLoS ONE. 2011;6:e23409.

    Article  Google Scholar 

  47. Kim K, Kim JM, Kim JS, Choi J, Lee YS, Neamati N, et al. VprBP has intrinsic kinase activity targeting histone H2A and represses gene transcription. Mol Cell. 2013;52:459–67.

    Article  CAS  PubMed  Google Scholar 

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Author contribution

YS designed the experiments. WA provided guidance throughout. YS, SK, NG, SR, and WA performed experiments and analyzed data. YS and WA wrote the manuscript.

Funding

This work was supported by NIH Grant AR073233 awarded to WA. The study was also partly supported by award number P30CA014089 from the National Cancer Institute.

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  1. Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    Yonghwan Shin, Sungmin Kim, Nikhil B. Ghate, Suhn K. Rhie & Woojin An

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  1. Yonghwan Shin
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Correspondence to Woojin An.

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Shin, Y., Kim, S., Ghate, N.B. et al. MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis. Oncogene 41, 560–570 (2022). https://doi.org/10.1038/s41388-021-02109-5

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