Tian Jianjun, Lin Yuting, Yu Jianhua
Clinical Laboratory, Qilu Children's Hospital of Shandong University, Jinan, 250000, Shandong, China.
Clinical Laboratory, Beihai Hospital of Yantai, Yantai, 264000, Shandong, China.
Biomed Pharmacother. 2017 Aug;92:919-926. doi: 10.1016/j.biopha.2017.05.118. Epub 2017 Jun 8.
MASTL (microtubule-associated serine/threonine kinase-like) is a critical kinase modulating mitotic entry. In this study, we investigated the mechanism of its dysregulation in breast cancer and its involvement in cisplatin resistance in ER+ breast cancer cells. Data mining in Kaplan-Meier Plotter showed that high MASTL expression was associated with worse distant metastasis free survival (DMFS) and relapse free survival (RFS) in ER+ breast cancer patients. In TCGA breast cancer cohort (TCGA-BRCA), MASTL was strongly co-upregulated with E2F8. High E2F8 expression was also strongly associated with unfavorable DMFS and RFS in ER+ breast cancer patients. Promoter scanning in JASPAR Database showed that the MASTL promoter region has a highly possible E2F8 binding site upstream the TSS site. The following western blot, dual luciferase assay and ChIP-qPCR validated this binding site. In MCF-7 cells, E2F8 overexpression alleviated cisplatin induced cell apoptosis by shortening G2/M arrest and promoting mitotic entry, the effect of which was largely canceled by inhibiting MASTL. Therefore, we infer that E2F8 can shorten cisplatin induced G2/M arrest by promoting MASTL mediated mitotic progression in ER+ breast cancer cells. These findings might help to explain why high MASTL or high E2F8 expression is associated with worse RFS in ER+ breast cancer.
微管相关丝氨酸/苏氨酸激酶样蛋白（MASTL）是一种调节有丝分裂进入的关键激酶。在本研究中，我们探究了其在乳腺癌中失调的机制及其在雌激素受体阳性（ER+）乳腺癌细胞顺铂耐药中的作用。在Kaplan-Meier Plotter数据库中进行数据挖掘发现，MASTL高表达与ER+乳腺癌患者较差的无远处转移生存期（DMFS）和无复发生存期（RFS）相关。在癌症基因组图谱（TCGA）乳腺癌队列（TCGA-BRCA）中，MASTL与E2F8强烈共上调。E2F8高表达也与ER+乳腺癌患者不良的DMFS和RFS密切相关。在JASPAR数据库中进行启动子扫描显示，MASTL启动子区域在转录起始位点（TSS）上游有一个高度可能的E2F8结合位点。随后的蛋白质免疫印迹、双荧光素酶测定和染色质免疫沉淀定量PCR（ChIP-qPCR）验证了该结合位点。在MCF-7细胞中，E2F8过表达通过缩短G2/M期阻滞和促进有丝分裂进入来减轻顺铂诱导的细胞凋亡，而抑制MASTL可在很大程度上消除这种作用。因此，我们推断E2F8可通过促进MASTL介导的有丝分裂进程来缩短ER+乳腺癌细胞中顺铂诱导的G2/M期阻滞。这些发现可能有助于解释为什么MASTL高表达或E2F8高表达与ER+乳腺癌患者较差的RFS相关。
