Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer.
Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer.
复制标题
靶向 HSP90-HDAC6 调节网络意味着乳腺癌的精准治疗
DOI：
10.7150/ijbs.18834
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发表时间：
2017
影响因子：
9.2
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Yu S;Cai X;Wu C;Liu Y;Zhang J;Gong X;Wang X;Wu X;Zhu T;Mo L;Gu J;Yu Z;Chen J;Thiery JP;Chai R;Chen L
乳腺癌是妇女死亡的主要原因。热休克蛋白90 （HSP90）和组蛋白去乙酰化酶6 （HDAC6）是很有前景的抗癌药物靶点。然而，抗hsp90和抗hdac6策略在乳腺癌精准治疗中的适用性尚不清楚。在本研究中，我们发现三阴性乳腺癌（triple negative breast cancer， TNBC）细胞在17-DMAG作用下，IC50值比ERα+乳腺癌细胞系T47D低7~40倍，细胞周期扰动更强，细胞凋亡增加，细胞迁移抑制更强，而T47D在Tubacin作用下，HDAC6表达比TNBC细胞高，抗癌反应更强。机制上，17-DMAG处理抑制了TNBC细胞中至少由ERK、AKT和Hippo通路组成的复杂网络，HDAC6的高表达通过使HSP90去乙酰化来抑制HSP90的活性。此外，我们发现HDAC6在他莫昔芬耐药T47D中的表达水平高于T47D，并且Tubacin在体内抑制了他莫昔芬耐药细胞的生长。我们的数据表明抗hsp90和抗hdac6分别是治疗TNBC和ERα+乳腺癌的有希望的策略，抗hdac6可以在治疗他莫昔芬耐药乳腺癌时考虑。
Breast cancer is the leading cause of women death. Heat shock protein 90 (HSP90) and Histone deacetylase 6 (HDAC6) are promising anti-cancer drug targets. However, it's still unclear the applicability of anti-HSP90 and anti-HDAC6 strategies in precision treatment of breast cancer. In current study, we found that triple negative breast cancer (TNBC) cells, compared to T47D, an ERα+ breast cancer cell line, exhibited 7~40 times lower IC50 values, stronger cell cycle perturbation, increased cell apoptosis and stronger inhibition of cell migration upon 17-DMAG treatment, while T47D, compared to TNBC cells, expressed higher HDAC6 and showed stronger anti-cancer response upon treatment of Tubacin. Mechanically, 17-DMAG treatment inhibited a complex network consists at least ERK, AKT, and Hippo pathway in TNBC cells, and higher expression of HDAC6 inhibited HSP90 activity via deacetylating HSP90. Furthermore, we found higher HDAC6 expression level in tamoxifen-resistance T47D than that in T47D, and Tubacin treatment suppressed the growth of tamoxifen-resistant cells in vivo. Our data suggested that anti-HSP90 and anti-HDAC6 are promising strategies to treat TNBC and ERα+ breast cancers respectively, and anti-HDAC6 can be considered during treatment of tamoxifen-resistance breast cancers.