他莫昔芬耐药仍然是雌激素受体阳性乳腺癌治疗的重大临床挑战。根据既往研究报告，雌激素受体阳性复发性乳腺癌的转录因子SOX9表达增加可以引起他莫昔芬耐药。不过，SOX9调控的具体机制尚不明确。
2019年11月6日，英国癌症研究基金会、英国《自然》旗下《英国癌症杂志》在线发表浙江大学医学院免疫学研究所、浙江大学医学院附属第二医院、浙江大学医学院附属第一医院、浙江大学医学院药理学系、美国范德堡大学医学院的研究报告，发现组蛋白脱乙酰酶HDAC5所致SOX9脱乙酰化并移动至细胞核对于乳腺癌他莫昔芬耐药至关重要。
该研究通过免疫沉淀法和蛋白质印迹法，测定SOX9的乙酰化水平；通过定量实时逆转录聚合酶链反应，分析组蛋白脱乙酰酶HDAC和二氢尿嘧啶脱氢酶依赖型脱乙酰酶SIRT的表达；通过二甲基噻唑二苯基四唑溴化物MTT染色法，测定细胞生长。通过荧光激活细胞分选法，分析醛脱氢酶阳性乳腺癌干细胞。通过免疫沉淀法，测定HDAC5与SOX9之间的相互作用。
结果发现，他莫昔芬耐药乳腺癌细胞的SOX9向细胞核移动需要脱乙酰化。此外，HDAC5是负责SOX9脱乙酰化以及随后向细胞核移动的关键脱乙酰酶。而且，转录因子C-MYC可以直接促进他莫昔芬耐药乳腺癌细胞的HDAC5表达。根据临床意义分析，SOX9和HDAC5表达水平较高与较低相比，他莫昔芬治疗乳腺癌患者的生存率较低。
因此，该研究结果表明，受到C-MYC调控的HDAC5对于SOX9脱乙酰化以及移动至细胞核至关重要，而后者对于他莫昔芬耐药至关重要，故针对C-MYC → HDAC5 → SOX9通路的靶向药物有望成为雌激素受体阳性乳腺癌治疗策略。
Br J Cancer. 2019 Nov 6. [Epub ahead of print]
HDAC5-mediated deacetylation and nuclear localisation of SOX9 is critical for tamoxifen resistance in breast cancer.
Yue Xue, Wenwen Lian, Jiaqi Zhi, Wenjuan Yang, Qianjin Li, Xingyi Guo, Jiahao Gao, Hao Qu, Weiqiang Lin, Zhongqi Li, Lihua Lai, Qingqing Wang.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; Vanderbilt University School of Medicine, Nashville, TN, USA; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University School of Medicine, Hangzhou, China.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
DOI: 10.1038/s41416-019-0625-0
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