ATF3 repression of BCL-XL determines apoptotic sensitivity to HDAC inhibitors across tumour types

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in AML, non-small cell lung cancer and estrogen receptor-positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherpy.  However, there is currently no clear strategy to reliably predict HDACi sensitivity. <p>In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumour type, and investigated the mechanism by which it triggers apoptosis.</p> <p>Experimental design: Fifty cancer cell lines from diverse tumour types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway. </p> <p>Results: We show that sensitivity to HDACi across tumour types is predicted by induction of the IE genes FOS, JUN and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the pro-apoptotic function of ATF3 is mediated through direct transcriptional repression of the pro-survival factor BCL-X_L (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-X_L which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumour cell types.</p> <p>Conclusions: These findings explain the heterogenous responses of tumour cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.

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