Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, Tokyo, Japan.
Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, Showa University School of Pharmacy, Tokyo, Japan.
Biochem Biophys Res Commun. 2023 Mar 15;649:1-9. doi: 10.1016/j.bbrc.2023.01.080. Epub 2023 Jan 26.
Aggressive cancers, such as triple-negative breast cancer (TNBC), are mostly fatal because of their potential 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 downstream 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.
侵袭性癌症，如三阴性乳腺癌（TNBC），由于其转移到远处器官的潜力而大多致命。癌细胞获得了各种转移的能力，包括对失巢凋亡（由细胞与细胞外基质的附着丧失引起的凋亡细胞死亡）的抵抗。转录共激活因子与 PDZ 结合基序（TAZ）和 Yes 相关蛋白（YAP）是 Hippo 通路的下游效应物，通过响应细胞的机械微环境，包括细胞与细胞外基质的相互作用，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 YAP 被无关激活，可能导致癌细胞的无锚定生存/增殖和转移进展。本研究旨在探讨 TAZ 和 YAP 在基底样（BL）TNBC 细胞中的失巢凋亡抵抗中的作用，BL-TNBC 细胞构成了 TNBC 的主要亚型（>70%）。我们发现 TAZ 和 YAP 在无锚定癌细胞存活或失巢凋亡抵抗中具有非冗余作用。特别是，TAZ 对于 BL-TNBC 细胞的失巢凋亡抵抗是必不可少的，但对于非转化的乳腺上皮细胞（MEC）的存活不是必需的。相反，TAZ 的同源物 YAP 对于非转化的 MEC 和癌细胞的存活都是必不可少的。因此，TAZ 可能是一种更理想的治疗靶点，可用于阻止侵袭性癌细胞的扩散，而不会杀死正常细胞。有趣的是，TAZ 在非贴壁条件下 BL-TNBC 细胞中异常稳定，促进了失巢凋亡抵抗。此外，去泛素化酶 OTUB1 负责附着 BL-TNBC 细胞中 TAZ 的稳定。重要的是，TAZ 和 OTUB1 的同时高表达与 BC 的不良预后相关。因此，OTUB1 已成为一个潜在的可用药靶。成功抑制 OTUB1 的酶活性有望下调 TAZ，并最终防止侵袭性癌症（如 BL-TNBC）的转移。
