AccScience Publishing / CP / Online First /
Submit to CP
Cite this article
122
Download
1033
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Cyclin-Dependent Kinase 8 (CDK8) Immunoexpression in Uveal Melanoma

Daniel M. Real1,2 ,  Edina A. Wappler-Guzzetta1,3 ,  Chelsea Huang1 ,  Aleksander M. Real4 ,  Jeremy K. Deisch1 ,  Justin C. Kerstetter1*
Show Less
1 Department of Pathology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
2 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA
4 Loma Linda University School of Medicine, Loma Linda, CA 92354, USA
CP 2023, 5(4), 2608
Submitted: 20 October 2023 | Accepted: 18 December 2023 | Published: 31 December 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Background: Cyclin-dependent kinase 8 (CKD8) is a component of the mediator complex, which regulates the gene transcription of nearly all RNA polymerase II-dependent genes. It is known to be overexpressed in more aggressive cutaneous melanomas, but no data exist for its uveal counterpart. Methods: Retrospective study on human UM tissue, performing CDK8 immunostaining (n=19). For analysis, a scale of 0-3 staining intensity was used along with an extent score, the percentage of positively staining cells (0-100%), and the confirmed pathological stages.  Results: No significant change was seen in the CDK8 staining patterns between the different pathologic stages, but there was a trend of higher pathological stage showing lower staining intensity score between the stages (p=0.06). Conclusions: Lower CDK8 immunoreactivity was associated with a trend for higher grade UM, highlighting the possible tumor suppressor role of CDK8 in UM advancement.

Keywords
Uveal melanoma
Ocular melanoma
Cyclin-dependent kinase 8 immunoexpression
Ocular oncology
Funding
No external funding or other financial support received.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. AJCC Cancer Staging Manual. New York, NY: Springer, 2016.

 

  1. Asturias FJ, Jiang YW, Myers LC, Gustafsson CM, Kornberg RD. "Conserved structures of mediator and RNA polymerase II holoenzyme." Science, 1999: 12;283(5404):985-7. doi: 10.1126/science.

 

  1. Atlas, Human Protein. MACROH2A1 protein expression summary - The Human Protein Atlas. April 5, 2022. https://www.proteinatlas.org/ENSG00000113648-H2AFY.

 

  1. Barbour H, Daou S, Hendzel M, Affar EB. "Polycomb group-mediated histone H2A monoubiquitination in epigenome regulation and nuclear processes." Nat Commun, 2020: 11(1):5947. doi: 10.1038/s41467-020-19722-9.

 

  1. Belle JI, Nijnik A. "H2A-DUBbing the mammalian epigenome: expanding frontiers for histone H2A deubiquitinating enzymes in cell biology and physiology." Int J Biochem Cell Biol, 2014: 50:161-74. doi: 10.1016/j.biocel.2014.03.004.

 

  1. Borggrefe T, Davis R, Erdjument-Bromage H, Tempst P, Kornberg RD. "A complex of the Srb8, -9, -10, and -11 transcriptional regulatory proteins from yeast." J Biol Chem, 2002: 277(46):44202-7. doi: 10.1074/jbc.M207195200.

 

  1. Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, Mazzoccoli G, Faulkes C, Pata I, Agodi A, Rezaee F, Minogue S, Warren A, Peterson A, Sedivy JM, Douet J, Buschbeck M, Cappello F, Mazza T, Pazienza V, Vinciguerra M. "DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy- Induced Senescence to Promote Hepatocellular Carcinoma Progression." Cancer Res, 2016: 76(3):594-606. doi: 10.1158/0008-5472.CAN-15-1336.

 

  1. Choudhary MM, Triozzi PL, Singh AD. "Uveal melanoma: evidence for adjuvant therapy." Int Ophthalmol Clin, 2015: 55(1):45-51. doi: 10.1097/IIO.0000000000000057.

 

  1. Costanzi C, Pehrson JR. "Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals ." Nature, 1998: 393(6685):599-601.

 

  1. Czegle I, Gray AL, Wang M, Liu Y, Wang J, Wappler- Guzzetta EA. "Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies." Life (Basel), 2021: 11(12):1351. doi: 10.3390/life11121351.

 

  1. Dotson MR, Yuan CX, Roeder RG, Myers LC, Gustafsson CM, Jiang YW, Li Y, Kornberg RD, Asturias FJ. "Structural organization of yeast and mammalian mediator complexes." Proc Natl Acad Sci U S A, 2000: 97(26):14307-10. doi: 10.1073/pnas.260489497.

 

  1. Ebmeier CC, Taatjes DJ. "Activator-Mediator binding regulates Mediator-cofactor interactions." Proc Natl Acad Sci U S A, 2010: 107(25):11283-8. doi: 10.1073/pnas. 0914215107.

 

  1. El Khattabi L, Zhao H, Kalchschmidt J, Young N, Jung S, Van Blerkom P, Kieffer-Kwon P, Kieffer-Kwon KR, Park S, Wang X, Krebs J, Tripathi S, Sakabe N, Sobreira DR, Huang SC, Rao SSP, Pruett N, Chauss D, Sadler E, Lopez A, Nóbrega MA, Aiden EL, Asturias FJ. "A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers." Cell, 2019: 178(5):1145-1158.e20. doi: 10.1016/j.cell.2019.07.011.

 

  1. Fan X, Chou DM, Struhl K. "Activator-specific recruitment of Mediator in vivo." Nat Struct Mol Biol, 2006: 13(2):117-20. doi: 10.1038/nsmb1049.

 

  1. Fant CB, Taatjes DJ. "Regulatory functions of the Mediator kinases CDK8 and CDK19." Transcription, 2019: 10(2):76-90. doi: 10.1080/21541264.2018.1556915.

 

  1. Fursova NA, Turberfield AH, Blackledge NP, Findlater EL, Lastuvkova A, Huseyin MK, Dobrinić P, Klose RJ. "BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome." Genes Dev, 2021: 35(9-10):749-770. doi: 10.1101/gad.347005.120.

 

  1. Giallongo S, Di Rosa M, Caltabiano R, Longhitano L, Reibaldi M, Distefano A, Lo Re O, Amorini AM, Puzzo L, Salvatorelli L, Palmucci S, Tibullo D, Russo A, Longo A, Lazzarino G, Li Volti G, Vinciguerra M. "Loss of macroH2A1 decreases mitochondrial metabolism and reduces the aggressiveness of uveal melanoma cells." Aging (Albany NY), 2020: 12(10):9745-9760. doi: 10.18632/ aging.103241.

 

  1. Group, Collaborative Ocular Melanoma Study. "Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15." Arch Ophthalmol , 2001: 119(5):670-6. doi: 10.1001/ archopht.119.5.670.

 

  1. Gu W, Wang C, Li W, Hsu FN, Tian L, Zhou J, Yuan C, Xie XJ, Jiang T, Addya S, Tai Y, Kong B, Ji JY. "Tumor-suppressive effects of CDK8 in endometrial cancer cells." Cell Cycle, 2013: 12(6):987-99. doi: 10.4161/ cc.24003.

 

  1. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM. "Frequent mutation of BAP1 in metastasizing uveal melanomas." Science, 2010: 330(6009):1410-3. doi: 10.1126/science.1194472.

 

  1. Hengartner CJ, Myer VE, Liao SM, Wilson CJ, Koh SS, Young RA. "Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases." Mol Cell, 1998: 2(1):43-53. doi: 10.1016/s1097-2765(00)80112-4.

 

  1. Herrspiegel C, See TRO, Mendoza PR, Grossniklaus HE, Stålhammar G. "Digital morphometry of tumor nuclei correlates to BAP-1 status, monosomy 3, gene expression class and survival in uveal melanoma." Exp Eye Res, 2020: 193:107987. doi: 10.1016/j.exer.2020.107987.

 

  1. Hirst M, Kobor MS, Kuriakose N, Greenblatt J, Sadowski I. "GAL4 is regulated by the RNA polymerase II holoenzyme-associated cyclin-dependent protein kinase SRB10/CDK8." Mol Cell, 1999: 3(5):673-8. doi: 10.1016/s1097-2765(00)80360-3.

 

  1. Jeronimo C, Langelier MF, Bataille AR, Pascal JM, Pugh BF, Robert F. "ail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo." Mol Cell, 2016: 64(3):455-466. doi: 10.1016/j.molcel.2016.09.002.

 

  1. Kaliki S, Shields CL. "Uveal melanoma: relatively rare but deadly cancer." Eye (Lond), 2017: 31(2):241-257. doi: 10.1038/eye.2016.275.

 

  1. Kalirai H, Dodson A, Faqir S, Damato BE, Coupland SE. "Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing." Br J Cancer, 2014: 111(7):1373-80. doi: 10.1038/bjc.2014.417.

 

  1. Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, Menendez S, Vardabasso C, Leroy G, Vidal CI, Polsky D, Osman I, Garcia BA, Hernando E, Bernstein E. "The histone variant macroH2A suppresses melanoma progression through regulation of CDK8." Nature, 2010: 468(7327):1105-9. doi: 10.1038/nature09590.

 

  1. Lapenna S, Giordano A. "Cell cycle kinases as therapeutic targets for cancer." Nat Rev Drug Discov, 2009: 8(7):547-66. doi: 10.1038/nrd2907.

 

  1. Lei S, Long J, Li J. "MacroH2A suppresses the proliferation of the B16 melanoma cell line." Mol Med Rep, 2014: 10(4):1845-50. doi: 10.3892/mmr.2014.2482.

 

  1. Liu Y, Kung C, Fishburn J, Ansari AZ, Shokat KM, Hahn S. "Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex." Mol Cell Biol, 2004: 24(4):1721-35. doi: 10.1128/ MCB.24.4.1721-1735.2004.

 

  1. Lo Re O, Vinciguerra M. "Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration." Genes (Basel), 2017: 8(12):367. doi: 10.3390/genes8120367.

 

  1. Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. "The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1." J Biol Chem, 2009: 284(49):34179-88. doi: 10.1074/jbc.M109.046755.

 

  1. McCleland ML, Soukup TM, Liu SD, Esensten JH, de Sousa e Melo F, Yaylaoglu M, Warming S, Roose-Girma M, Firestein R. "Cdk8 deletion in the Apc(Min) murine tumour model represses EZH2 activity and accelerates tumourigenesis." J Pathol, 2015: 237(4):508-19. doi: 10.1002/path.4596.

 

  1. Menzl I, Witalisz-Siepracka A, Sexl V. "CDK8-Novel Therapeutic Opportunities." Pharmaceuticals (Basel), 2019: 12(2):92. doi: 10.3390/ph12020092.

 

  1. Park SJ, Shim JW, Park HS, Eum DY, Park MT, Mi Yi J, Choi SH, Kim SD, Son TG, Lu W, Kim ND, Yang K, Heo K. "MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B." Oncogene, 2016: 35(10):1292-301. doi: 10.1038/onc.2015.18.

 

  1. Petrenko N, Jin Y, Wong KH, Struhl K. "Mediator Undergoes a Compositional Change during Transcriptional Activation." Mol Cell, 2016: 64(3):443-454. doi: 10.1016/j.molcel.2016.09.015.

 

  1. Rohde JR, Trinh J, Sadowski I. "Multiple signals regulate GAL transcription in yeast ." Mol Cell Biol, 2000: 20(11):3880-6. doi: 10.1128/MCB.20.11.3880-3886.2000.

 

  1. Salvatorelli L, Puzzo L, Bartoloni G, Palmucci S, Longo A, Russo A, Reibaldi M, Vinciguerra M, Li Volti G, Caltabiano R. "Immunoexpression of Macroh2a in Uveal Melanoma." Applied Sciences, 2019: 9(16):3244. https://doi.org/ 10.3390/app9163244.

 

  1. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J. "Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB." Nature, 2010: 465(7295):243-7. doi: 10.1038/nature08966.

 

  1. Silva-Rodríguez P, Fernández-Díaz D, Bande M, Pardo M, Loidi L, Blanco-Teijeiro MJ. "GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma." Cancers (Basel), 2022: 14(13):3066. doi: 10.3390/cancers14133066.

 

  1. Singh AD, Turell ME, Topham AK. "Uveal melanoma: trends in incidence, treatment, and survival." Ophthalmology, 2011: 118(9):1881-5. doi: 10.1016/ j.ophtha.2011.01.040.

 

  1. Stålhammar G, See TRO, Phillips SS, Grossniklaus HE. "Density of PAS positive patterns in uveal melanoma: Correlation with vasculogenic mimicry, gene expression class, BAP-1 expression, macrophage infiltration, and risk for metastasis." Mol Vis, 2019: 25:502-516.

 

  1. Steinparzer I, Sedlyarov V, Rubin JD, Eislmayr K, Galbraith MD, Levandowski CB, Vcelkova T, Sneezum L, Wascher F, Amman F, Kleinova R, Bender H, Andrysik Z, Espinosa JM, Superti-Furga G, Dowell RD, Taatjes DJ, Kovarik P. "Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions." Mol Cell, 2019: 76(3):485-499.e8. doi: 10.1016/j.molcel.2019.07.034.

 

  1. Szalai E, Wells JR, Ward L, Grossniklaus HE. "Uveal Melanoma Nuclear BRCA1-Associated Protein-1 Immunoreactivity Is an Indicator of Metastasis." Ophthalmology, 2018: 125(2):203-209. doi: 10.1016/ j.ophtha.2017.07.018.

 

  1. Thomas S, Pütter C, Weber S, Bornfeld N, Lohmann DR, Zeschnigk M. "Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study." Br J Cancer, 2012: 106(6):1171-6. doi: 10.1038/bjc.2012.54.

 

  1. van de Nes JA, Nelles J, Kreis S, Metz CH, Hager T, Lohmann DR, Zeschnigk M. "Comparing the Prognostic Value of BAP1 Mutation Pattern, Chromosome 3 Status, and BAP1 Immunohistochemistry in Uveal Melanoma." Am J Surg Pathol, 2016: 40(6):796-805. doi: 10.1097/ PAS.0000000000000645.

 

  1. Verger A, Monté D, Villeret V. "Twenty years of Mediator complex structural studies." Biochem Soc Trans, 2019: 47(1):399-410. doi: 10.1042/BST20180608.

 

  1. Vincent O, Kuchin S, Hong SP, Townley R, Vyas VK, Carlson M. "Interaction of the Srb10 kinase with Sip4, a transcriptional activator of gluconeogenic genes in Saccharomyces cerevisiae." Mol Cell Biol, 2001: 21(17):5790-6. doi: 10.1128/MCB.21.17.5790-5796.2001.

 

  1. Xu W, Ji JY. "Dysregulation of CDK8 and Cyclin C in tumorigenesis." J Genet Genomics, 2011: 38(10):439-52. doi: 10.1016/j.jgg.2011.09.002.

 

  1. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD. "Formation of MacroH2A-containing senescence- associated heterochromatin foci and senescence driven by ASF1a and HIRA." Dev Cell, 2005: 8(1):19-30. doi: 10.1016/j.devcel.2004.10.019.

 

  1. Zhou Y, Nelson AC, He Y, Munro SA, Song KY, Domingo-Musibay E, Giubellino A. "Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions." Genes (Basel), 2021: 13(1):10. doi: 10.3390/genes13010010.
Share
Back to top
Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept