Epigenetic Silencing of Claudin-6 Promotes Anchorage-independent Growth of Breast Carcinoma Cells

Overview

Journal Cancer Sci

Specialty Oncology

Date 2007 Jul 25

PMID 17645772

Citations 36

Authors

Makoto Osanai

Masaki Murata

Hideki Chiba

Takashi Kojima

Norimasa Sawada

Affiliations

Soon will be listed here.

Abstract

Cancer cells often exhibit loss of functional tight junctions (TJ), and disruption of the TJ structure is associated with cancer development. However, whether loss of a certain type of claudin, an integral membrane protein of TJ, is involved in malignant phenotypes remains to be clarified. Based on a report that claudin-6 functions as a tumor suppressor for breast cancer, the authors show here that suppression of claudin-6 expression results in increased resistance to various apoptogens, and causally enhances anchorage-independent growth properties. Because claudin-6 expression is partially silenced by promoter CpG island hypermethylation in MCF7 breast carcinoma cells, a synergistic effect of a demethylator and histone deacetylase inhibitor up-regulates the expression of endogenous claudin-6, which is sufficient for apoptotic sensitization and abrogation of colony-forming efficacy. In addition, decreased expression of claudin-6 promotes cellular invasiveness and transendothelial migration, accompanied by an increase in matrix metalloproteinase activity. These data suggest that the methylator phenotype of claudin-6 may at least partially contribute to enhanced tumorigenic and invasive properties of breast carcinoma cells.

Citing Articles

Expression and Targeted Application of Claudins Family in Hepatobiliary and Pancreatic Diseases.

Du F, Xie Y, Wu S, Ji M, Dong B, Zhu C J Hepatocell Carcinoma. 2024; 11:1801-1821.

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Expression patterns of claudins in cancer.

Tao D, Guan B, Li H, Zhou C Heliyon. 2023; 9(11):e21338.

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Twist1‑mediated transcriptional activation of Claudin‑4 promotes cervical cancer cell migration and invasion.

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Claudin-4: A New Molecular Target for Epithelial Cancer Therapy.

Fujiwara-Tani R, Mori S, Ogata R, Sasaki R, Ikemoto A, Kishi S Int J Mol Sci. 2023; 24(6).

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Estrogen Receptor and Claudin-6 Might Play Vital Roles for Long-Term Prognosis in Patients With Luminal A Breast Cancer Who Underwent Neoadjuvant Chemotherapy.

Liu Y, Kang Y, Li J, Zhang Y, Jia S, Sun Q Front Oncol. 2022; 12:630065.

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References

Hoevel T, Macek R, Swisshelm K, Kubbies M . Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids. Int J Cancer. 2003; 108(3):374-83. DOI: 10.1002/ijc.11571. View

Tokes A, Kulka J, Paku S, Szik A, Paska C, Novak P . Claudin-1, -3 and -4 proteins and mRNA expression in benign and malignant breast lesions: a research study. Breast Cancer Res. 2005; 7(2):R296-305. PMC: 1064136. DOI: 10.1186/bcr983. View

Saitou M, Furuse M, Sasaki H, Schulzke J, Fromm M, Takano H . Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell. 2000; 11(12):4131-42. PMC: 15062. DOI: 10.1091/mbc.11.12.4131. View

Osanai M, Petkovich M . Expression of the retinoic acid-metabolizing enzyme CYP26A1 limits programmed cell death. Mol Pharmacol. 2005; 67(5):1808-17. DOI: 10.1124/mol.104.005769. View

Kramer F, White K, Kubbies M, Swisshelm K, Weber B . Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer. Hum Genet. 2000; 107(3):249-56. DOI: 10.1007/s004390000375. View

Macrae M, Neve R, Rodriguez-Viciana P, Haqq C, Yeh J, Chen C . A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell. 2005; 8(2):111-8. DOI: 10.1016/j.ccr.2005.07.005. View

Tobioka H, Isomura H, Kokai Y, Tokunaga Y, Yamaguchi J, Sawada N . Occludin expression decreases with the progression of human endometrial carcinoma. Hum Pathol. 2004; 35(2):159-64. DOI: 10.1016/j.humpath.2003.09.013. View

Tanaka M, Kamata R, Sakai R . EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005; 280(51):42375-82. DOI: 10.1074/jbc.M503786200. View

Hough C, Pizer E, Montz F, Im D, Rosenshein N, Cho K . Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res. 2000; 60(22):6281-7. View

10.

Matter K, Aijaz S, Tsapara A, Balda M . Mammalian tight junctions in the regulation of epithelial differentiation and proliferation. Curr Opin Cell Biol. 2005; 17(5):453-8. DOI: 10.1016/j.ceb.2005.08.003. View

11.

Zelinski D, Zantek N, Stewart J, Irizarry A, Kinch M . EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001; 61(5):2301-6. View

12.

Matter K, Balda M . Signalling to and from tight junctions. Nat Rev Mol Cell Biol. 2003; 4(3):225-36. DOI: 10.1038/nrm1055. View

13.

Clark S, Harrison J, Paul C, Frommer M . High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 1994; 22(15):2990-7. PMC: 310266. DOI: 10.1093/nar/22.15.2990. View

14.

Miyamori H, Takino T, Kobayashi Y, Tokai H, Itoh Y, Seiki M . Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases. J Biol Chem. 2001; 276(30):28204-11. DOI: 10.1074/jbc.M103083200. View

15.

Quan C, Lu S . Identification of genes preferentially expressed in mammary epithelial cells of Copenhagen rat using subtractive hybridization and microarrays. Carcinogenesis. 2003; 24(10):1593-9. DOI: 10.1093/carcin/bgg129. View

16.

Issa J . CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004; 4(12):988-93. DOI: 10.1038/nrc1507. View

17.

Morin P . Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res. 2005; 65(21):9603-6. DOI: 10.1158/0008-5472.CAN-05-2782. View

18.

Li D, Mrsny R . Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin. J Cell Biol. 2000; 148(4):791-800. PMC: 2169369. DOI: 10.1083/jcb.148.4.791. View

19.

Tsukita S, Furuse M, Itoh M . Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001; 2(4):285-93. DOI: 10.1038/35067088. View

20.

Michl P, Barth C, Buchholz M, Lerch M, Rolke M, Holzmann K . Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res. 2003; 63(19):6265-71. View