Abstract 2629: Sustained immediate-early gene induction is linked to histone deacetylase inhibitor-induced apoptosis in multiple tumour types

Abstract

Abstract Introduction: Histone deacetylase inhibitors (HDACi) are a novel class of cancer therapeutics, currently approved for the treatment of cutaneous T-cell lymphoma (CTCL) and undergoing clinical trials for other haematological and solid tumours. Through screening of a panel of 30 colorectal cancer cell (CRC) lines, we previously established that HDACi-induced apoptosis is linked to a specific transcriptional response consisting of induction of multiple immediate-early (IE) and stress response genes. The purpose of this study was to investigate whether the findings made in colorectal cancer cells are applicable to other tumor types and to further elucidate the mechanism of apoptosis induction involving IE genes. Results: We screened a panel of 40 tumor cell lines including that of CTCL, multiple myeloma, NSCLC, melanoma, breast and prostate cancer, for HDACi (sodium butyrate and Vorinostat) sensitivity by PI/FACS analysis and identified highly sensitive and resistant cell lines. Consistent with the findings made in CRCs, quantitative RT-PCR analysis revealed that the expression of six representative IE genes (Fos, Jun, Atf3, Egr1, Egr3, Gadd45b) were preferentially induced by HDACi treatment in the 5 most sensitive cell lines compared to the 5 most refractory tumor cell lines. To study kinetics of IE gene induction, we performed time-course experiments on cancer cell lines treated with various stimuli, including EGF, phorbol ester PMA, and HDACi. While EGF and PMA induce IE gene expression in a rapid and transient manner, HDACi-induction of IE gene expression is sustained over 24 hours, suggesting that the prolonged expression of these genes may be responsible for apoptosis induction. By transient transfection of siRNA into tumour cell lines, we demonstrated that the down-regulation of the IE genes Jun and Atf3 partially blocks HDACi-induced apoptosis. Conclusions: We demonstrated that HDACi-induced apoptosis is linked to sustained transcriptional induction of multiple IE genes in a variety of cancer cells. Furthermore, we demonstrated that IE genes of the AP-1 transcription factor family Jun and Atf3 are directly involved in the apoptosis response induced upon HDACi treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2629. doi:10.1158/1538-7445.AM2011-2629