Makena Monish Ram, Ko Myungjun, Dang Donna Kimberly, Rao Rajini
Department of Physiology, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USA.
Cancers (Basel). 2021 Jan 12;13(2):259. doi: 10.3390/cancers13020259.
The secretory pathway Ca-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca levels to activate downstream components of non-canonical Wnt/Ca signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca signaling pathways to reverse EMT in breast tumors.
分泌途径Ca-ATP酶SPCA2是三受体阴性乳腺癌（TNBC）中的一种肿瘤抑制因子，TNBC是一种侵袭性很强的分子亚型，缺乏针对性的治疗方案。TNBC中SPCA2的低表达预示着患者的生存预后较差。先前的研究已经证实，将SPCA2重新导入TNBC细胞可恢复基础钙信号，抑制间充质基因表达，减轻体外肿瘤迁移和体内转移。在本研究中，我们检测了组蛋白去乙酰化酶抑制剂（HDACi）对TNBC细胞系的影响。我们发现，泛HDACi伏立诺他和I类HDACi罗米地辛可诱导SPCA2转录本的剂量依赖性上调，同时下调间充质标志物和具有上皮表型特征的肿瘤细胞迁移。沉默SPCA2消除了HDACi逆转上皮-间充质转化（EMT）的能力。不依赖于ATP酶活性，SPCA2提高静息钙水平以激活非经典Wnt/Ca信号的下游成分。HDACi处理导致CAMKII和β-连环蛋白的SPCA2依赖性磷酸化，从而关闭Wnt信号。我们得出结论，SPCA2通过一种新的非经典Wnt/Ca信号模式介导HDACi在TNBC中逆转EMT的功效。我们的研究结果为筛选利用钙信号通路逆转乳腺肿瘤EMT的表观遗传调节剂提供了依据。
