Abstract
Background
Advanced basal cell carcinomas (BCCs) suffer from a scarcity of effective treatment options. Previously, we found that the targetable histone methyltransferase EZH2 was upregulated in aggressive BCC subtypes, suggesting that epigenetics may play a role in BCC progression. The purpose of this study was to determine whether EZH2-associated proteins and marks may be employed for the stratification of BCC histologic subtypes.
Methods
Sixty-two specimens (from 61 patients), representing more or less aggressive BCC histologic subtypes and matching non-malignant epidermal cells, were included in this study. Immunohistochemistry of H3K27me3, 5hmC, NSD2, MOF and JARID1B was performed to assess their putative associations with BCC histologic subtypes, as well as with EZH2 and Ki67 expression levels.
Results
We found that H3K27me3 and 5hmC upregulation was positively correlated with the occurrence of a less aggressive BCC histology. The modifications were also positively correlated with each other. Interestingly, we found that they were negatively correlated with the expression of EZH2, a marker for an aggressive BCC histology. The levels of NSD2, MOF, H3K27me3 and 5hmC were found to be universally upregulated in BCCs versus non-malignant epidermal cells.
Conclusions
Our data reveal an EZH2-associated epigenetic marker profile that correlates with histologic signs of BCC aggressiveness. Our findings may have diagnostic and therapeutic implications, and indicate that epigenetic markers may be shared even with relatively less aggressive tumor types, thereby suggesting universal themes.
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References
R.C. Rao, M.P. Chan, C.A. Andrews, A. Kahana, EZH2, proliferation rate, and aggressive tumor subtypes in cutaneous basal cell carcinoma. JAMA Oncol. 2, 962–963 (2016). https://doi.org/10.1001/jamaoncol.2016.0021
A. Sekulic, D. Von Hoff, Hedgehog pathway inhibition. Cell 164, 831 (2016). https://doi.org/10.1016/j.cell.2016.02.021
K. Holm, D. Grabau, K. Lovgren, S. Aradottir, S. Gruvberger-Saal, J. Howlin, L.H. Saal, S.P. Ethier, P.O. Bendahl, O. Stal, P. Malmstrom, M. Ferno, L. Ryden, C. Hegardt, A. Borg and M. Ringner, Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes. Mol Oncol. 6, 494-506 (2012). https://doi.org/10.1016/j.molonc.2012.06.002
R. Margueron, G. Li, K. Sarma, A. Blais, J. Zavadil, C.L. Woodcock, B.D. Dynlacht, D. Reinberg, Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32, 503–518 (2008). https://doi.org/10.1016/j.molcel.2008.11.004
Y. Xiang, Z. Zhu, G. Han, X. Ye, B. Xu, Z. Peng, Y. Ma, Y. Yu, H. Lin, A.P. Chen and C.D. Chen, JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 104, 19226-19231 (2007). https://doi.org/10.1073/pnas.0700735104
M.S. Banck, S. Li, H. Nishio, C. Wang, A.S. Beutler, M.J. Walsh, The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics 4, 100–106 (2009)
I.A. Asangani, B. Ateeq, Q. Cao, L. Dodson, M. Pandhi, L.P. Kunju, R. Mehra, R.J. Lonigro, J. Siddiqui, N. Palanisamy, Y.M. Wu, X. Cao, J.H. Kim, M. Zhao, Z.S. Qin, M.K. Iyer, C.A. Maher, C. Kumar-Sinha, S. Varambally, A.M. Chinnaiyan, Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol. Cell 49, 80–93 (2013). https://doi.org/10.1016/j.molcel.2012.10.008
Q. Li, H. Sun, Y. Shu, X. Zou, Y. Zhao, C. Ge, hMOF (human males absent on the first), an oncogenic protein of human oral tongue squamous cell carcinoma, targeting EZH2 (enhancer of zeste homolog 2). Cell Prolif. 48, 436–442 (2015). https://doi.org/10.1111/cpr.12177
F. Neri, D. Incarnato, A. Krepelova, S. Rapelli, A. Pagnani, R. Zecchina, C. Parlato, S. Oliviero, Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. Genome Biol. 14, R91 (2013). https://doi.org/10.1186/gb-2013-14-8-r91
S.G. Jin, Y. Jiang, R. Qiu, T.A. Rauch, Y. Wang, G. Schackert, D. Krex, Q. Lu, G.P. Pfeifer, 5-hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res. 71, 7360–7365 (2011). https://doi.org/10.1158/0008-5472.CAN-11-2023
O.A. Bamodu, W.C. Huang, W.H. Lee, A. Wu, L.S. Wang, M. Hsiao, C.T. Yeh, T.Y. Chao, Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448. BMC Cancer, 10.1186/s12885-016-2108-5 16, 160 (2016)
K. Xu, Z.J. Wu, A.C. Groner, H.H. He, C. Cai, R.T. Lis, X. Wu, E.C. Stack, M. Loda, T. Liu, H. Xu, L. Cato, J.E. Thornton, R.I. Gregory, C. Morrissey, R.L. Vessella, R. Montironi, C. Magi-Galluzzi, P.W. Kantoff, S.P. Balk, X.S. Liu, M. Brown, EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469 (2012). https://doi.org/10.1126/science.1227604
T. Swigut, J. Wysocka, H3K27 demethylases, at long last. Cell 131, 29–32 (2007). https://doi.org/10.1016/j.cell.2007.09.026
K.H. Kim, C.W. Roberts, Targeting EZH2 in cancer. Nat. Med 22, 128–134 (2016). https://doi.org/10.1038/nm.4036
E. di Luccio, Inhibition of nuclear receptor binding SET domain 2/multiple myeloma SET domain by LEM-06 implication for epigenetic cancer therapies. J. Cancer Prev. 20, 113–120 (2015). https://doi.org/10.15430/JCP.2015.20.2.113
A. Tumber, A. Nuzzi, E.S. Hookway, S.B. Hatch, S. Velupillai, C. Johansson, A. Kawamura, P. Savitsky, C. Yapp, A. Szykowska, N. Wu, C. Bountra, C. Strain-Damerell, N.A. Burgess-Brown, G.F. Ruda, O. Fedorov, S. Munro, K.S. England, R.P. Nowak, C.J. Schofield, N.B. La Thangue, C. Pawlyn, F. Davies, G. Morgan, N. Athanasou, S. Muller, U. Oppermann, P.E. Brennan, Potent and selective KDM5 inhibitor stops cellular demethylation of H3K4me3 at transcription start sites and proliferation of MM1S myeloma cells. Cell Chem. Biol. 24, 371–380 (2017). https://doi.org/10.1016/j.chembiol.2017.02.006
Acknowledgements
Supported in part by the National Institutes of Health (P30CA046592) VISORB clinical trial (ClinicalTrials.gov Identifier: NCT02436408; A.K. principal investigator) with support from Genentech, Inc. A.K. is supported by the Forbes Cancer Research Institute and the A. Alfred Taubman Medical Research Institute. A.K. is recipient of a Clinician-Scientist Award from Research to Prevent Blindness (RPB), and R.C.R. is a recipient of an RPB Career Development Award. R.C.R. is supported by Career Development Awards from the National Institutes of Health (K08EY026654) and the A. Alfred Taubman Medical Research Institute, where he is the Leslie and Abigail Wexner Emerging Scholar. R.C.R. received funding from the Leonard G. Miller Ophthalmic Research Fund at the Kellogg Eye Center, Grossman Research Fund, Barbara Dunn Research Fund, Roz Greenspoon Research Fund, Beatrice & Reymont Paul Foundation and March Hoops to Beat Blindness. The authors acknowledge generous support from an unrestricted research grant from RPB to the Department of Ophthalmology and Visual Sciences at the University of Michigan. None of the sponsors participated in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript; and the decision to submit the manuscript for publication.
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R.C.R. and A.K. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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Rao, R.C., Chan, M.P., Andrews, C.A. et al. Epigenetic markers in basal cell carcinoma: universal themes in oncogenesis and tumor stratification? - a short report. Cell Oncol. 41, 693–698 (2018). https://doi.org/10.1007/s13402-018-0402-8
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DOI: https://doi.org/10.1007/s13402-018-0402-8