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Epigenetic Modulation of Retinoic Acid Receptor ß2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma

Authors' Affiliations: ¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and ² Nihon Schering K.K., Kobe, Japan

Requests for reprints: Roberto Pili, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, 1M52, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-502-7482; Fax: 410-614-8160; E-mail: piliro{at}jhmi.edu.

Purpose: Histone deacetylase (HDAC) inhibitors have been shown to reverse epigenetic repression of certain genes, including retinoic acid receptor ß2 (RARß2). In this study, we examined whether RARß2 expression is repressed in human renal cell carcinoma (RCC) and whether the HDAC inhibitor MS-275 may revert its epigenetic repression.

Experimental Design: Six human tumor RCC cell lines were analyzed for RARß2 gene expression and for methylation and acetylation status at the promoter level. Modulation of RARß2 expression and correlation with antitumor activity by combination of MS-275 with 13-cis-retinoic acid (CRA) was assessed in a RARß2-negative RCC cell line.

Results: RARß2 expression was either strongly present, weakly expressed, or absent in the RCC cell lines analyzed. Methylation-specific PCR indicated that the RARß2 promoter was partially methylated in three of the cell lines. CRA treatment did not inhibit clonogenic growth in the RARß2-negative cell line RCC1.18, whereas MS-275 induced a dose-dependent inhibitory effect. A greater inhibitory effect was observed with combination treatment (MS-275 + CRA). Treatment with MS-275 was associated with histone acetylation at the promoter level and synergistic gene reexpression of RARß2 in combination with CRA. RARß2 reexpression was associated with synergistic induction of the retinoid-responsive gene HOXA5. In vivo, single-agent CRA treatment showed no significant effect, whereas MS-275 and the combination induced a regression of RCC1.18 tumor xenografts. Discontinuation of treatment produced tumor recurrence in MS-275-treated mice, whereas animals treated with the combination remained tumor free.

Conclusion: The HDAC inhibitor MS-275 seems to revert retinoid resistance due to epigenetic silencing of RARß2 in a human RCC model and has greater antitumor activity in combination with CRA compared with single agents. Thus, the combination of HDAC inhibitors and retinoids may represent a novel therapeutic approach in patients with RCC.

Key Words: Histone deacetylase inhibitor • retinoic acid receptor • renal cell carcinoma

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