MST1 下调多发性骨髓瘤中的 TAZ 肿瘤抑制蛋白，是一个潜在的治疗靶点。

MST1 downregulates TAZ tumor suppressor protein in multiple myeloma and is a potential therapeutic target.

机构信息

Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada; Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada.

Cytel Inc, Toronto, Ontario, Canada.

出版信息

Exp Hematol. 2023 Jul;123:34-45. doi: 10.1016/j.exphem.2023.04.004. Epub 2023 May 1.

DOI:10.1016/j.exphem.2023.04.004

PMID:37137439

Abstract

We have previously reported that transcriptional activator with PDZ-binding motif (TAZ) functions as a tumor suppressor in multiple myeloma (MM). MST1 is a serine-threonine kinase upstream of the Hippo-signaling pathway that functions as a tumor suppressor in many non-hematologic malignancies. However, its role in hematologic malignancies, including MM is still poorly understood. In this article, we provide evidence that MST1 expression is higher in MM and negatively correlates with TAZ expression in both cell lines and patient samples. High MST1 expression was associated with poor clinical outcomes. Genetic or pharmacologic inhibition of MST1 leads to increased TAZ expression and cell death. Importantly, MST1 inhibitors sensitize myeloma cells to frontline antimyeloma agents-lenalidomide and dexamethasone. Taken together, our data reveal a key role for MST1 in MM pathogenesis and provide evidence to explore the therapeutic potential of using MST inhibitors to upregulate TAZ expression in MM to promote response to anticancer agents.

摘要

我们之前曾报道过，PDZ 结合基序转录激活因子（TAZ）在多发性骨髓瘤（MM）中作为肿瘤抑制因子发挥作用。MST1 是 Hippo 信号通路的上游丝氨酸-苏氨酸激酶，在许多非血液系统恶性肿瘤中作为肿瘤抑制因子发挥作用。然而，其在包括 MM 在内的血液系统恶性肿瘤中的作用仍知之甚少。在本文中，我们提供的证据表明，MST1 在 MM 中的表达水平更高，并且在细胞系和患者样本中与 TAZ 的表达呈负相关。高 MST1 表达与不良的临床结果相关。MST1 的遗传或药物抑制导致 TAZ 表达增加和细胞死亡。重要的是，MST1 抑制剂可使骨髓瘤细胞对一线抗骨髓瘤药物来那度胺和地塞米松敏感。综上所述，我们的数据揭示了 MST1 在 MM 发病机制中的关键作用，并提供了证据来探索使用 MST 抑制剂上调 MM 中 TAZ 表达以促进对抗癌药物反应的治疗潜力。