Tamoxifen resistance remains a significant clinical challenge for the therapy of ER-positive breast cancer. It has been reported that the upregulation of transcription factor SOX9 in ER+ recurrent cancer is sufficient for tamoxifen resistance. However, the mechanisms underlying the regulation of SOX9 remain largely unknown.
The acetylation level of SOX9 was detected by immunoprecipitation and western blotting. The expressions of HDACs and SIRTs were evaluated by qRT-PCR. Cell growth was measured by performing MTT assay. ALDH-positive breast cancer stem cells were evaluated by flow cytometry. Interaction between HDAC5 and SOX9 was determined by immunoprecipitation assay.
Deacetylation is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. Furthermore, HDAC5 is the key deacetylase responsible for SOX9 deacetylation and subsequent nuclear translocation. In addition, the transcription factor C-MYC directly promotes the expression of HDAC5 in tamoxifen resistant breast cancer cells. For clinical relevance, high SOX9 and HDAC5 expression are associated with lower survival rates in breast cancer patients treated with tamoxifen.
This study reveals that HDAC5 regulated by C-MYC is essential for SOX9 deacetylation and nuclear localisation, which is critical for tamoxifen resistance. These results indicate a potential therapy strategy for ER+ breast cancer by targeting C-MYC/HDAC5/SOX9 axis.
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The authors declare no competing interests.
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The human data involved in current study are obtained and analysed from the publicly archived datasets. There are no animal data in current study.
This work was supported by grants from the National Program on Key Basic Research Project (2014CB542101), National Natural Science Foundation of China (81230074, 81373115), Zhejiang Public Welfare Technology Research Project (GF19H160090) and Natural Science Foundation of Zhejiang Province (LY15H160012).
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The datasets used and analysed during current study are available from the corresponding authors on reasonable request. The hyperlinks of publicly archived datasets involved in this study are as follows: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9195; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9574; http://molonc.bccrc.ca/aparicio-lab/research/metabric/
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Xue, Y., Lian, W., Zhi, J. et al. HDAC5-mediated deacetylation and nuclear localisation of SOX9 is critical for tamoxifen resistance in breast cancer. Br J Cancer (2019) doi:10.1038/s41416-019-0625-0