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Arch Dermatol. 2011 Apr;147(4):443-9. doi: 10.1001/archdermatol.2010.376. Epub 2010 Dec 20.

Reduction of Fas/CD95 promoter methylation, upregulation of Fas protein, and enhancement of sensitivity to apoptosis in cutaneous T-cell lymphoma.

Author information

  • 1Departments of Dermatology, University of Wisconsin, and Veterans Affairs Medical Center, Madison, WI 53715, USA.

Abstract

OBJECTIVE:

To explore the relationships among (Fas) promoter methylation, Fas expression, and apoptotic sensitivity in cutaneous T-cell lymphoma (CTCL).

DESIGN:

Laboratory investigation.

SETTING:

Dermatology research unit of a university medical center.

SAMPLES:

Five CTCL lines and S├ęzary syndrome blood.

INTERVENTIONS:

Treatment of cells with 5-azacytidine (aza), methotrexate, and interferon alfa-2b.

MAIN OUTCOME MEASURES:

Fas promoter methylation, Fas expression, and sensitivity to Fas-mediated apoptosis.

RESULTS:

Fas promoter methylation correlates inversely with the level of Fas transcript, protein, and apoptotic sensitivity in CTCL. Increased DNA methylation also correlates with decreased NFkB (nuclear factor kappa-light chain enhancer of activated B cells) binding to the Fas promoter. All of these relationships were reversed by the DNA-demethylating agent, 5-aza. We found that methotrexate also functions as a DNA-demethylating agent by depleting methyl donors and, together with interferon alfa-2b, upregulates Fas and enhances sensitivity to Fas-mediated apoptosis.

CONCLUSIONS:

These findings help explain the previously reported impressive responses of patients with advanced CTCL to combination therapy with methotrexate and interferon alfa. They also provide a new rationale for the treatment of CTCL with methotrexate and its use in combination with other agents.

PMID:
21173302
[PubMed - indexed for MEDLINE]
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