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Cited by 88Ferroptosis and cancer prognosisIron Metabolism and DisordersFerrocene Chemistry and Applications

MLL4 mediates differentiation and tumor suppression through ferroptosis

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Egolf, Shaun, Zou, Jonathan, Anderson, Amy, Simpson, Cory L., Aubert, Yann, Prouty, Stephen, Ge, Kai, Seykora, John T. +1 more·2021·Science Advances
DOI 10.1126/sciadv.abj9141PMC PMC8664260
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Abstract

This study reveals how epigenetic errors drive skin cancer initiation via altered cell fate and impaired ferroptosis.

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  • MLL4 binding at enhancers coincides with the binding of master regulators.

    “MLL4 binding at enhancers has been shown to coincide with the binding of master regulators42–44.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [43]

    The Results section reports that MLL4 binds enhancers and that motifs for the master epithelial regulator p63 and for p53 are enriched at MLL4 binding sites. It also reports interactions between MLL4 and those factors, but motif enrichment and protein interaction do not establish that the factors bind the same enhancers at the same time. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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  1. [1]D. Hanahan, R. A. Weinberg, Hallmarks of cancer: The next generation. Cell 144, 646– 674 (2011). 21376230
  2. [2]J. D. Campbell, C. Yau, R. Bowlby, Y. Liu, K. Brennan, H. Fan, A. M. Taylor, C. Wang, V. Walter, R. Akbani, L. A. Byers, C. J. Creighton, C. Coarfa, J. Shih, A. D. Cherniack, O. Gevaert, M. Prunello, H. Shen, P. Anur, J. Chen, H. Cheng, D. N. Hayes, S. Bullman, C. S. Pedamallu, A. I. Ojesina, S. Sadeghi, K. L. Mungall, A. G. Robertson, C. Benz, A. Schultz, R. S. Kanchi, C. M. Gay, A. Hegde, L. Diao, J. Wang, W. Ma, P. Sumazin, H. S. Chiu, T. W. Chen, P. Gunaratne, L. Donehower, J. S. Rader, R. Zuna, H. Al-Ahmadie, A. J. Lazar, E. R. Flores, K. Y. Tsai, J. H. Zhou, A. K. Rustgi, E. Drill, R. Shen, C. K. Wong; Cancer Genome Atlas Research Network, J. M. Stuart, P. W. Laird, K. A. Hoadley, J. N. Weinstein, M. Peto, C. R. Pickering, Z. Chen, C. Van Waes, Genomic, pathway network, and immunologic features distinguishing squamous carcinomas. Cell Rep. 23, 194– 212.e6 (2018). 29617660 PMC6002769
  3. [3]I. Bartha, J. di Iulio, J. C. Venter, A. Telenti, Human gene essentiality. Nat. Rev. Genet. 19, 51– 62 (2018). 29082913
  4. [4]J. E. Lee, C. Wang, S. Xu, Y. W. Cho, L. Wang, X. Feng, A. Baldridge, V. Sartorelli, L. Zhuang, W. Peng, K. Ge, H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013). 24368734 PMC3869375
  5. [5]R. J. Fagan, A. K. Dingwall, COMPASS ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer. Cancer Lett. 458, 56– 65 (2019). 31128216 PMC6638576
  6. [6]D. J. Ford, A. K. Dingwall, The cancer COMPASS: Navigating the functions of MLL complexes in cancer. Cancer Genet. 208, 178– 191 (2015). 25794446
  7. [7]E. Cerami, J. Gao, U. Dogrusoz, B. E. Gross, S. O. Sumer, B. A. Aksoy, A. Jacobsen, C. J. Byrne, M. L. Heuer, E. Larsson, Y. Antipin, B. Reva, A. P. Goldberg, C. Sander, N. Schultz, The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401– 404 (2012). 22588877 PMC3956037
  8. [8]J. Gao, B. A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S. O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). 23550210 PMC4160307
  9. [9]J. G. Tate, S. Bamford, H. C. Jubb, Z. Sondka, D. M. Beare, N. Bindal, H. Boutselakis, C. G. Cole, C. Creatore, E. Dawson, P. Fish, B. Harsha, C. Hathaway, S. C. Jupe, C. Y. Kok, K. Noble, L. Ponting, C. C. Ramshaw, C. E. Rye, H. E. Speedy, R. Stefancsik, S. L. Thompson, S. Wang, S. Ward, P. J. Campbell, S. A. Forbes, COSMIC: The Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 47, D941– D947 (2019). 30371878 PMC6323903
  10. [10]J. C. Fowler, C. King, C. Bryant, M. W. J. Hall, R. Sood, S. H. Ong, E. Earp, D. Fernandez-Antoran, J. Koeppel, S. C. Dentro, D. Shorthouse, A. Durrani, K. Fife, E. Rytina, D. Milne, A. Roshan, K. Mahububani, K. Saeb-Parsy, B. A. Hall, M. Gerstung, P. H. Jones, Selection of oncogenic mutant clones in normal human skin varies with body site. Cancer Discov. 11, 340– 361 (2021). 33087317 PMC7116717
  11. [13]Y. Y. Li, G. J. Hanna, A. C. Laga, R. I. Haddad, J. H. Lorch, P. S. Hammerman, Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin. Cancer Res. 21, 1447– 1456 (2015). 25589618 PMC4359951
  12. [14]C. R. Pickering, J. H. Zhou, J. J. Lee, J. A. Drummond, S. A. Peng, R. E. Saade, K. Y. Tsai, J. L. Curry, M. T. Tetzlaff, S. Y. Lai, J. Yu, D. M. Muzny, H. Doddapaneni, E. Shinbrot, K. R. Covington, J. Zhang, S. Seth, C. Caulin, G. L. Clayman, A. K. El-Naggar, R. A. Gibbs, R. S. Weber, J. N. Myers, D. A. Wheeler, M. J. Frederick, Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin. Cancer Res. 20, 6582– 6592 (2014). 25303977 PMC4367811
  13. [15]A. S. Yilmaz, H. G. Ozer, J. L. Gillespie, D. C. Allain, M. N. Bernhardt, K. C. Furlan, L. T. Castro, S. B. Peters, P. Nagarajan, S. Y. Kang, O. H. Iwenofu, T. Olencki, T. N. Teknos, A. E. Toland, Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors. Cancer 123, 1184– 1193 (2017). 27906449 PMC5360561
  14. [16]K. S. Nehal, C. K. Bichakjian, Update on keratinocyte carcinomas. N. Engl. J. Med. 379, 363– 374 (2018). 30044931
  15. [17]E. Lin-Shiao, Y. Lan, M. Coradin, A. Anderson, G. Donahue, C. L. Simpson, P. Sen, R. Saffie, L. Busino, B. A. Garcia, S. L. Berger, B. C. Capell, KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes Dev. 32, 181– 193 (2018). 29440247 PMC5830930
  16. [18]Y. Jang, A. Broun, C. Wang, Y.-K. Park, L. Zhuang, J.-E. Lee, E. Froimchuk, C. Liu, K. Ge, H3.3K4M destabilizes enhancer H3K4 methyltransferases MLL3/MLL4 and impairs adipose tissue development. Nucleic Acids Res. 47, 607– 620 (2019). 30335158 PMC6344897
  17. [19]C. Darido, S. R. Georgy, S. M. Jane, The role of barrier genes in epidermal malignancy. Oncogene 35, 5705– 5712 (2016). 27041586
  18. [20]K. R. Feingold, P. M. Elias, Role of lipids in the formation and maintenance of the cutaneous permeability barrier. Biochim. Biophys. Acta 1841, 280– 294 (2014). 24262790
  19. [21]P. Krieg, G. Furstenberger, The role of lipoxygenases in epidermis. Biochim. Biophys. Acta 1841, 390– 400 (2014). 23954555
  20. [22]N. Dang, D. F. Murrell, Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa. Exp. Dermatol. 17, 553– 568 (2008). 18558993
  21. [23]K. M. Eckl, P. Krieg, W. Kuster, H. Traupe, F. Andre, N. Wittstruck, G. Furstenberger, H. C. Hennies, Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum. Mutat. 26, 351– 361 (2005). 16116617
  22. [24]J. Fischer, B. Bouadjar, R. Heilig, M. Huber, C. Lefevre, F. Jobard, F. Macari, A. Bakija-Konsuo, F. Ait-Belkacem, J. Weissenbach, M. Lathrop, D. Hohl, J. F. Prud’homme, Mutations in the gene encoding SLURP-1 in Mal de Meleda. Hum. Mol. Genet. 10, 875– 880 (2001). 11285253
  23. [25]S. R. Nagarajan, L. M. Butler, A. J. Hoy, The diversity and breadth of cancer cell fatty acid metabolism. Cancer Metab 9, 2 (2021). 33413672 PMC7791669
  24. [26]C. Wang, L. Shao, C. Pan, J. Ye, Z. Ding, J. Wu, Q. Du, Y. Ren, C. Zhu, Elevated level of mitochondrial reactive oxygen species via fatty acid β-oxidation in cancer stem cells promotes cancer metastasis by inducing epithelial-mesenchymal transition. Stem Cell Res. Ther. 10, 175 (2019). 31196164 PMC6567550
  25. [27]M. Chen, J. Huang, The expanded role of fatty acid metabolism in cancer: New aspects and targets. Precis. Clin. Med. 2, 183– 191 (2019). 31598388 PMC6770278
  26. [28]B. M. Stevens, C. L. Jones, D. A. Pollyea, R. Culp-Hill, A. D’Alessandro, A. Winters, A. Krug, D. Abbott, M. Goosman, S. Pei, H. Ye, A. E. Gillen, M. W. Becker, M. R. Savona, C. Smith, C. T. Jordan, Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat. Cancer 1, 1176– 1187 (2020). 33884374 PMC8054994
  27. [29]G. Bergers, S. M. Fendt, The metabolism of cancer cells during metastasis. Nat. Rev. Cancer 21, 162– 180 (2021). 33462499 PMC8733955
  28. [31]G. Pascual, A. Avgustinova, S. Mejetta, M. Martin, A. Castellanos, C. S. Attolini, A. Berenguer, N. Prats, A. Toll, J. A. Hueto, C. Bescos, L. Di Croce, S. A. Benitah, Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41– 45 (2017). 27974793
  29. [32]R. P. Charles, M. Guitard, C. Leyvraz, B. Breiden, M. Haftek, Z. Haftek-Terreau, J. C. Stehle, K. Sandhoff, E. Hummler, Postnatal requirement of the epithelial sodium channel for maintenance of epidermal barrier function. J. Biol. Chem. 283, 2622– 2630 (2008). 18039670
  30. [33]L. Szymanski, R. Skopek, M. Palusinska, T. Schenk, S. Stengel, S. Lewicki, L. Kraj, P. Kaminski, A. Zelent, Retinoic acid and its derivatives in skin. Cell 9, 2660 (2020). PMC7764495 33322246
  31. [34]J. Lee, P. K. Saha, Q. H. Yang, S. Lee, J. Y. Park, Y. Suh, S. K. Lee, L. Chan, R. G. Roeder, J. W. Lee, Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 19229– 19234 (2008). 19047629 PMC2614744
  32. [35]S. Lee, D. K. Lee, Y. Dou, J. Lee, B. Lee, E. Kwak, Y. Y. Kong, S. K. Lee, R. G. Roeder, J. W. Lee, Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases. Proc. Natl. Acad. Sci. U.S.A. 103, 15392– 15397 (2006). 17021013 PMC1622834
  33. [36]B. Chu, N. Kon, D. Chen, T. Li, T. Liu, L. Jiang, S. Song, O. Tavana, W. Gu, ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat. Cell Biol. 21, 579– 591 (2019). 30962574 PMC6624840
  34. [37]X. Jiang, B. R. Stockwell, M. Conrad, Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266– 282 (2021). 33495651 PMC8142022
  35. [38]B. R. Stockwell, X. Jiang, W. Gu, Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 30, 478– 490 (2020). 32413317 PMC7230071
  36. [39]E. Ferretti, E. De Smaele, L. Di Marcotullio, I. Screpanti, A. Gulino, Hedgehog checkpoints in medulloblastoma: The chromosome 17p deletion paradigm. Trends Mol. Med. 11, 537– 545 (2005). 16290230
  37. [40]C. S. Tam, S. Stilgenbauer, How best to manage patients with chronic lymphocytic leuekmia with 17p deletion and/or TP53 mutation? Leuk. Lymphoma 56, 587– 593 (2015). 25641428
  38. [41]Y. Guo, X. Zhang, W. Tan, X. Miao, T. Sun, D. Zhao, D. Lin, Platelet 12-lipoxygenase Arg261Gln polymorphism: functional characterization and association with risk of esophageal squamous cell carcinoma in combination with COX-2 polymorphisms. Pharmacogenet. Genomics 17, 197– 205 (2007). 17460548
  39. [42]W. S. Yang, B. R. Stockwell, Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 26, 165– 176 (2016). 26653790 PMC4764384
  40. [43]A. M. Savino, S. I. Fernandes, O. Olivares, A. Zemlyansky, A. Cousins, E. K. Markert, S. Barel, I. Geron, L. Frishman, Y. Birger, C. Eckert, S. Tumanov, G. MacKay, J. J. Kamphorst, P. Herzyk, J. Fernández-García, I. Abramovich, I. Mor, M. Bardini, E. Barin, S. Janaki-Raman, J. R. Cross, M. G. Kharas, E. Gottlieb, S. Izraeli, C. Halsey, Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on stearoyl CoA desaturase. Nat. Cancer 1, 998– 1009 (2020). 33479702 PMC7116605
  41. [44]L. Tesfay, B. T. Paul, A. Konstorum, Z. Deng, A. O. Cox, J. Lee, C. M. Furdui, P. Hegde, F. M. Torti, S. V. Torti, Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 79, 5355– 5366 (2019). 31270077 PMC6801059
  42. [45]H. Feng, B. R. Stockwell, Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 16, e2006203 (2018). 29795546 PMC5991413
  43. [46]C. L. Simpson, S. Kojima, S. Getsios, RNA interference in keratinocytes and an organotypic model of human epidermis. Methods Mol. Biol. 585, 127– 146 (2010). 19908001
  44. [47]M. Uhlen, L. Fagerberg, B. M. Hallstrom, C. Lindskog, P. Oksvold, A. Mardinoglu, A. Sivertsson, C. Kampf, E. Sjostedt, A. Asplund, I. Olsson, K. Edlund, E. Lundberg, S. Navani, C. A. Szigyarto, J. Odeberg, D. Djureinovic, J. O. Takanen, S. Hober, T. Alm, P. H. Edqvist, H. Berling, H. Tegel, J. Mulder, J. Rockberg, P. Nilsson, J. M. Schwenk, M. Hamsten, K. von Feilitzen, M. Forsberg, L. Persson, F. Johansson, M. Zwahlen, G. von Heijne, J. Nielsen, F. Pontén, Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015). 25613900
  45. [48]E. Soares, H. Zhou, Master regulatory role of p63 in epidermal development and disease. Cell. Mol. Life Sci. 75, 1179– 1190 (2018). 29103147 PMC5843667
  46. [49]S. Kim, I. F. Choi, J. R. Quante, L. Zhang, D. R. Roop, M. I. Koster, p63 directly induces expression of Alox12, a regulator of epidermal barrier formation. Exp. Dermatol. 18, 1016– 1021 (2009). 19555433 PMC2857403
  47. [50]R. Kumar, L. Coronel, B. Somalanka, A. Raju, O. A. Aning, O. An, Y. S. Ho, S. Chen, S. Y. Mak, P. Y. Hor, H. Yang, M. Lakshmanan, H. Itoh, S. Y. Tan, Y. K. Lim, A. P. C. Wong, S. H. Chew, T. H. Huynh, B. C. Goh, C. Y. Lim, V. Tergaonkar, C. F. Cheok, Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat. Commun. 9, 3931 (2018). 30258081 PMC6158291
  48. [51]W. Wang, M. Green, J. E. Choi, M. Gijon, P. D. Kennedy, J. K. Johnson, P. Liao, X. Lang, I. Kryczek, A. Sell, H. Xia, J. Zhou, G. Li, J. Li, W. Li, S. Wei, L. Vatan, H. Zhang, W. Szeliga, W. Gu, R. Liu, T. S. Lawrence, C. Lamb, Y. Tanno, M. Cieslik, E. Stone, G. Georgiou, T. A. Chan, A. Chinnaiyan, W. Zou, CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270– 274 (2019). 31043744 PMC6533917
  49. [52]Z. Dou, C. Xu, G. Donahue, T. Shimi, J. A. Pan, J. Zhu, A. Ivanov, B. C. Capell, A. M. Drake, P. P. Shah, J. M. Catanzaro, M. D. Ricketts, T. Lamark, S. A. Adam, R. Marmorstein, W.-X. Zong, T. Johansen, R. D. Goldman, P. D. Adams, S. L. Berger, Autophagy mediates degradation of nuclear lamina. Nature 527, 105– 109 (2015). 26524528 PMC4824414
  50. [53]M. I. Love, W. Huber, S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). 25516281 PMC4302049
  51. [54]B. C. Capell, A.M. Drake, J. Zhu, P. P. Shah, Z. Dou, J. Dorsey, D. F. Simola, G. Donahue, M. Sammons, T. S. Rai, C. Natale, T. W. Ridky, P. D. Adams, S. L. Berger, MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 30, 321– 336 (2016). 26833731 PMC4743061
  52. [55]S. Egolf, Y. Aubert, M. Doepner, A. Anderson, A. Maldonado-Lopez, G. Pacella, J. Lee, E. K. Ko, J. Zou, Y. Lan, C. L. Simpson, T. Ridky, B. C. Capell, LSD1 inhibition promotes epithelial differentiation through derepression of fate-determining transcription factors. Cell Rep. 28, 1981– 1992.e7 (2019). 31433976 PMC6719800
  53. [56]B. Langmead, S. L. Salzberg, Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357– 359 (2012). 22388286 PMC3322381
  54. [57]H. Li, B. Handsaker, A. Wysoker, T. Fennell, J. Ruan, N. Homer, G. Marth, G. Abecasis, R. Durbin; 1000 Genome Project Data Processing Subgroup, The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078– 2079 (2009). 19505943 PMC2723002
  55. [58]S. Heinz, C. Benner, N. Spann, E. Bertolino, Y. C. Lin, P. Laslo, J. X. Cheng, C. Murre, H. Singh, C. K. Glass, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576– 589 (2010). 20513432 PMC2898526

Cited by

Sorted by citations

Authors
Egolf, S., Zou, J., Anderson, A., Simpson, C. L., Aubert, Y., Prouty, S., Ge, K., Seykora, J. T., & Capell, B. C.
Affiliations
  • University of Pennsylvania (US)
  • National Institutes of Health (US)
  • Abramson Cancer Center (US)
Corresponding author
Capell, Brian C.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-12-10
Volume
7
Issue
50
Pages
eabj9141-eabj9141
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abj9141
PMC
PMC8664260
OpenAlex
W4200570453
Cited by
88
References
3
Citations by year
2026: 14 · 2025: 20 · 2024: 26 · 2023: 18 · 2022: 10
FWCI
8.73
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute of Environmental Health Sciences (R01ES028114)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR070289, K08AR075846, R01AR077615, P30AR069589, T32AR007465)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Physical Sciences › Chemistry › Organic Chemistry › Ferrocene Chemistry and Applications
Keywords
KMT2D, ferroptosis, tumor suppression, cell differentiation, skin homeostasis, histone methyltransferase, skin cancer

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