Histone deacetylase inhibitor romidepsin induces efficient tumor cell lysis via selective down-regulation of LMP1 and c-myc expression in EBV-positive diffuse large B-cell lymphoma. Issue 2 (10th August 2015)

• Record Type: Journal Article
• Authors: Shin, Dong-Yeop; Kim, Areumnuri; Kang, Hye Jin; Park, Sunhoo; Kim, Dong Wan; Lee, Seung-Sook
• Is Part Of: Cancer letters. Volume 364:Issue 2(2015)
• Page Start: 89
• Page End: 97
• Publication Date: 2015-08-10
• Subjects: c-myc -- Diffuse large B-cell lymphoma -- Epstein–Barr virus -- Latent membrane protein-1 -- Romidepsin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.03.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Novel treatment strategy for overcoming poor prognosis of EBV-positive DLBCL is needed. The histone deacetylase inhibitor romidepsin shows selective cytotoxicity in EBV-positive DLBCL. Romidepsin inhibits the expression of LMP1 and c-myc in EBV-positive cells. Dual inhibition of LMP1 and c-myc activates EBV lytic cycle in EBV-positive cells. Romidepsin could be a promising agent for treating EBV-positive DLBCL. Abstract: We investigated the role of the histone deacetylase inhibitor, romidepsin, in Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma with poor clinical outcomes. We used EBV-positive and EBV-negative DLBCL cell lines and generated two EBV-transfected cell lines, LY7/EBV and U2932/EBV. Romidepsin was cytotoxic to cultured EBV-positive cells via the activation of the caspase cascade . Moreover, in vivo mice xenograft models demonstrated the cytotoxicity of romidepsin to EBV-positive DLBCL cells. Romidepsin induced cytotoxicity via the reduction of LMP1 and c-myc expression in EBV-positive cells. Inhibiting either LMP1 or c-myc using small inhibitory RNAs caused partial cytotoxicity in EBV-positive Farage and U2932/EBV lines. The dual inhibition of LMP1 and c-myc showed a synergistic cytotoxic effect in EBV-positive cells similar in magnitude to that of romidepsin alone. In addition, either double blockade of LMP1 and c-myc activity or romidepsin single treatment activated EBV lytic cycle in EBV-positive cells. In conclusion, romidepsin exerts strong anti-tumor activity in EBV-positive DLBCL via the inhibition of both LMP1 and c-myc. Our findings indicate that romidepsin might be a promising treatment for EBV-positive DLBCL.