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

Chueh, AC; Tse, JW; Dickinson, M; Ioannidis, P; Jenkins, L; Togel, L; Tan, B; Luk, I; Davalos-Salas, M; Nightingale, R; Thompson, MR; Williams, BR; Lessene, G; Lee, EF; Fairlie, WD; Dhillon, AS; Mariadason, JM

Author(s): Chueh, AC; Tse, JW; Dickinson, M; Ioannidis, P; Jenkins, L; Togel, L; Tan, B; Luk, I; Davalos-Salas, M; Nightingale, R; Thompson, MR; Williams, BR; Lessene, G; Lee, EF; Fairlie, WD; Dhillon, AS; Mariadason, JM;
Details: Publication Year 2017-09-15,Volume 23,Issue #18,Page 5573-5584
Journal Title: Clinical Cancer Research
Publication Type: Journal Article
Abstract: 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. 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. 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. 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-XL (BCL2L1) These findings provided the rationale for dual inhibition of HDAC and BCL-XL which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumour cell types. 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.
Publisher: AACR
Research Division(s): Chemical Biology
PubMed ID: 28611196
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-17-0466
NHMRC Grants: NHMRC/1008833, NHMRC/1066665,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-06-26 02:15:21

Last Modified: 2020-04-07 02:10:12