Regulation of Pancreatic Tumor Cell Proliferation and Chemoresistance by the Histone Methyltransferase Enhancer of Zeste Homologue 2

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2008 Nov 5

PMID 18980972

Citations 84

Authors

Andrei V Ougolkov

Vladimir N Bilim

Daniel D Billadeau

Affiliations

Soon will be listed here.

Abstract

Purpose: Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells.

Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival.

Results: We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P<0.001). We found that genetic depletion of EZH2 results in reexpression of p27(Kip1) and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer.

Conclusions: Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27(Kip1) as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.

Citing Articles

Spatial recognition and semi-quantification of epigenetic events in pancreatic cancer subtypes with multiplexed molecular imaging and machine learning.

Szymonski K, Janiszewska N, Sofinska K, Skirlinska-Nosek K, Lupa D, Czaja M Sci Rep. 2025; 15(1):6518.

PMID: 39987295 PMC: 11846859. DOI: 10.1038/s41598-025-90087-z.

PRMT1 promotes epigenetic reprogramming associated with acquired chemoresistance in pancreatic cancer.

Nguyen C, Colon-Emeric B, Murakami S, Shujath M, Yi C Cell Rep. 2024; 43(5):114176.

PMID: 38691454 PMC: 11238875. DOI: 10.1016/j.celrep.2024.114176.

Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma.

Cheng Y, Song Z, Fang X, Tang Z Clin Epigenetics. 2024; 16(1):54.

PMID: 38600608 PMC: 11007890. DOI: 10.1186/s13148-024-01666-2.

PRMT1 promotes pancreatic cancer development and resistance to chemotherapy.

Ku B, Eisenbarth D, Baek S, Jeong T, Kang J, Hwang D Cell Rep Med. 2024; 5(3):101461.

PMID: 38460517 PMC: 10983040. DOI: 10.1016/j.xcrm.2024.101461.

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.

Chibaya L, Murphy K, DeMarco K, Gopalan S, Liu H, Parikh C Nat Cancer. 2023; 4(6):872-892.

PMID: 37142692 PMC: 10516132. DOI: 10.1038/s43018-023-00553-8.

References

Hu Y, Watanabe H, Li P, Wang Y, Ohtsubo K, Yamaguchi Y . An immunohistochemical analysis of p27 expression in human pancreatic carcinomas. Pancreas. 2000; 21(3):226-30. DOI: 10.1097/00006676-200010000-00002. View

Cardoso C, Mignon C, Hetet G, Grandchamps B, Fontes M, Colleaux L . The human EZH2 gene: genomic organisation and revised mapping in 7q35 within the critical region for malignant myeloid disorders. Eur J Hum Genet. 2000; 8(3):174-80. DOI: 10.1038/sj.ejhg.5200439. View

Visser H, Gunster M, Kluin-Nelemans H, Manders E, Raaphorst F, Meijer C . The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br J Haematol. 2001; 112(4):950-8. DOI: 10.1046/j.1365-2141.2001.02641.x. View

Jaffee E, Hruban R, Canto M, Kern S . Focus on pancreas cancer. Cancer Cell. 2002; 2(1):25-8. DOI: 10.1016/s1535-6108(02)00093-4. View

Varambally S, Dhanasekaran S, Zhou M, Barrette T, Kumar-Sinha C, Sanda M . The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419(6907):624-9. DOI: 10.1038/nature01075. View

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P . Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298(5595):1039-43. DOI: 10.1126/science.1076997. View

Kleer C, Cao Q, Varambally S, Shen R, Ota I, Tomlins S . EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003; 100(20):11606-11. PMC: 208805. DOI: 10.1073/pnas.1933744100. View

Zakaria S, Gomez T, Savoy D, McAdam S, Turner M, Abraham R . Differential regulation of TCR-mediated gene transcription by Vav family members. J Exp Med. 2004; 199(3):429-34. PMC: 2211790. DOI: 10.1084/jem.20031228. View

Raaphorst F, Meijer C, Fieret E, Blokzijl T, Mommers E, Buerger H . Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene. Neoplasia. 2004; 5(6):481-8. PMC: 1502571. DOI: 10.1016/s1476-5586(03)80032-5. View

10.

Ougolkov A, Zhang B, Yamashita K, Bilim V, Mai M, Fuchs S . Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer. J Natl Cancer Inst. 2004; 96(15):1161-70. DOI: 10.1093/jnci/djh219. View

11.

Dignam J, Lebovitz R, Roeder R . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983; 11(5):1475-89. PMC: 325809. DOI: 10.1093/nar/11.5.1475. View

12.

Armstrong D, Kaufmann S, Ottaviano Y, Furuya Y, Buckley J, Isaacs J . Epidermal growth factor-mediated apoptosis of MDA-MB-468 human breast cancer cells. Cancer Res. 1994; 54(20):5280-3. View

13.

Pagano M, Tam S, Theodoras A, Del Sal G, Chau V, Yew P . Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995; 269(5224):682-5. DOI: 10.1126/science.7624798. View

14.

Loda M, Cukor B, Tam S, Lavin P, Fiorentino M, Draetta G . Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997; 3(2):231-4. DOI: 10.1038/nm0297-231. View

15.

Kollmannsberger C, Peters H, Fink U . Chemotherapy in advanced pancreatic adenocarcinoma. Cancer Treat Rev. 1998; 24(2):133-56. DOI: 10.1016/s0305-7372(98)90079-2. View

16.

Sherr C, Roberts J . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999; 13(12):1501-12. DOI: 10.1101/gad.13.12.1501. View

17.

Ougolkov A, Fernandez-Zapico M, Savoy D, Urrutia R, Billadeau D . Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 2005; 65(6):2076-81. DOI: 10.1158/0008-5472.CAN-04-3642. View

18.

Axanova L, Morre D, Morre D . Growth of LNCaP cells in monoculture and coculture with osteoblasts and response to tNOX inhibitors. Cancer Lett. 2005; 225(1):35-40. DOI: 10.1016/j.canlet.2004.11.017. View

19.

Santos-Rosa H, Caldas C . Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer. 2005; 41(16):2381-402. DOI: 10.1016/j.ejca.2005.08.010. View

20.

Raman J, Mongan N, Tickoo S, Boorjian S, Scherr D, Gudas L . Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res. 2005; 11(24 Pt 1):8570-6. DOI: 10.1158/1078-0432.CCR-05-1047. View