An indispensable role of TAZ in anoikis resistance promoted by OTUB1 deubiquitinating enzyme in basal-like triple-negative breast cancer cells
An indispensable role of TAZ in anoikis resistance promoted by OTUB1 deubiquitinating enzyme in basal-like triple-negative breast cancer cells
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DOI：
10.1016/j.bbrc.2023.01.080
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发表时间：
2023-02-02
影响因子：
3.1
通讯作者：
Shibanuma, Motoko
中科院分区：
文献类型：
--
作者：
Nakagawa, Hidetsugu;Higurashi, Masato;Shibanuma, Motoko
侵袭性癌症，如三阴性乳腺癌（TNBC），大多是致命的，因为它们有可能转移到远处器官。癌细胞获得各种转移能力，包括对失巢凋亡的抗性，失巢凋亡是由失去对细胞外基质的锚定诱导的凋亡性细胞死亡。PDZ结合基序转录辅激活因子（TAZ）和Yes相关蛋白（雅普）是Hippo信号通路的下游效应因子，通过响应细胞的力学微环境（包括细胞与细胞外基质的相互作用）来调节细胞和组织水平的结构。Hippo通路在癌细胞中经常被破坏，TAZ和雅普被不相关地激活，可能导致癌细胞的锚定非依赖性存活/增殖和转移进展。该研究旨在研究TAZ和雅普在基底样（BL）TNBC细胞中的抗失巢凋亡中的作用，所述基底样（BL）TNBC细胞包括TNBC的主要亚型（> 70%）。我们发现TAZ和雅普在锚定非依赖性癌细胞存活或抗失巢凋亡中具有非冗余作用。特别地，TAZ对于BL-TNBC细胞中的失巢凋亡抗性是必不可少的，但对于非转化的乳腺上皮细胞（MEC）的存活不是。相比之下，TAZ的一个副产物雅普对于非转化MEC和癌细胞的存活都是不可或缺的。因此，TAZ可能是一个较好的治疗靶点，在不杀死正常细胞的情况下，对抗侵袭性癌细胞的扩散。有趣的是，TAZ在非贴壁条件下在BL-TNBC细胞中异常稳定，这促进了抗失巢凋亡。此外，OTUB 1，一种去泛素化酶，负责TAZ在分离的BL-TNBC细胞中的稳定。重要的是，TAZ和OTUB 1同时高表达与BC的不良预后相关。因此，OTUB 1已经成为一个潜在的药物靶点。成功抑制OTUB 1酶活性有望下调TAZ，并最终预防侵袭性癌症（如BL-TNBC）的转移。(c)2023作者爱思唯尔公司出版这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Aggressive cancers, such as triple-negative breast cancer (TNBC), are mostly fatal because of their po-tential to metastasize to distant organs. Cancer cells acquire various abilities to metastasize, including resistance to anoikis, an apoptotic cell death induced by loss of anchorage to the extracellular matrix. Transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP), the down-stream effectors of the Hippo pathway, regulate cell-and tissue-level architectures by responding to mechanical microenvironments of cells, including the cell-extracellular matrix interaction. The Hippo pathway is frequently disrupted in cancer cells, and TAZ and YAP are irrelevantly activated, potentially resulting in anchorage-independent survival/proliferation of cancer cells and metastatic progression. The study aims to investigate the roles of TAZ and YAP in anoikis resistance in basal-like (BL) TNBC cells, which comprise a major subtype (>70%) of TNBC. We found that TAZ and YAP had nonredundant roles in anchorage-independent cancer cell survival or anoikis resistance. Particularly, TAZ was indispensable for anoikis resistance in BL-TNBC cells but not for survival of non-transformed mammary epithelial cells (MECs). In contrast, YAP, a paralog of TAZ, was indispensable for survival of both non-transformed MECs and cancer cells. Therefore, TAZ might be a preferable therapeutic target against dissemination of aggressive cancer cells without killing normal cells. Interestingly, TAZ was abnormally stabilized in BL-TNBC cells under non-adherent conditions, which promoted anoikis resistance. Furthermore, OTUB1, a deubiquitinating enzyme, was responsible for the stabilization of TAZ in detached BL-TNBC cells. Importantly, simultaneous high expression of TAZ and OTUB1 was associated with poor prognosis in BC. Thus, OTUB1 has emerged as a potentially druggable target. Successful inhibition of OTUB1 enzymatic activity is expected to downregulate TAZ and eventually prevents metastasis of aggressive cancers, such as BL-TNBC.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).