Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, 21999, Republic of Korea.
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
Cell Death Dis. 2021 May 8;12(5):461. doi: 10.1038/s41419-021-03757-x.
DNAJB9, a member of the heat shock protein 40 family, acts as a multifunctional player involved in the maintenance of their client proteins and cellular homeostasis. However, the mechanistic action of DNAJB9 in human malignancies is yet to be fully understood. In this study, we found that ectopic restoration of DNAJB9 inhibits the migration, invasion, in vivo metastasis, and lung colonization of triple-negative breast cancer (TNBC) cells. Mechanistically, DNAJB9 stabilizes FBXO45 protein by suppressing self-ubiquitination and reduces the abundance of ZEB1 by Lys48-linked polyubiquitination to inhibit the epithelial-mesenchymal transition (EMT) and metastasis. Clinically, the reduction of DNAJB9 expression, concomitant with decreased FBXO45 abundance in breast cancer tissues, correlates with poorer clinical outcomes of patients with breast cancer. Taken together, our results provide a novel insight into the metastasis of TNBC and define a promising therapeutic strategy for cancers with overactive ZEB1 by regulating the DNAJB9-FBXO45 signaling axis.
DNAJB9 是热休克蛋白 40 家族的成员，作为一种多功能蛋白，参与维持其客户蛋白和细胞内稳态。然而，DNAJB9 在人类恶性肿瘤中的作用机制尚未完全阐明。在这项研究中，我们发现 DNAJB9 的异位恢复抑制了三阴性乳腺癌（TNBC）细胞的迁移、侵袭、体内转移和肺定植。从机制上讲，DNAJB9 通过抑制自身泛素化稳定 FBXO45 蛋白，并通过 Lys48 连接的多泛素化减少 ZEB1 的丰度，从而抑制上皮-间充质转化（EMT）和转移。临床上，DNAJB9 表达的降低伴随着乳腺癌组织中 FBXO45 丰度的降低，与乳腺癌患者的临床结局较差相关。综上所述，我们的研究结果为 TNBC 的转移提供了新的见解，并通过调控 DNAJB9-FBXO45 信号轴，为 ZEB1 过度激活的癌症提供了一种有前途的治疗策略。
