Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 Nansihuan Xilu, Beijing, 100070, China.
Department of Orthopaedic Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111 Xianxia Road, Shanghai, 200336, China.
Cell Death Dis. 2021 Jul 30;12(8):753. doi: 10.1038/s41419-021-04026-7.
Chordoma is a rare bone malignancy with a high rate of local recurrence and distant metastasis. Although DEP domain-containing protein 1B (DEPDC1B) is implicated in a variety of malignancies, its relationship with chordoma is unclear. In this study, the biological role and molecular mechanism of DEPDC1B in chordoma were explored. The function of DEPDC1B in chordoma cells was clarified through loss-of-function assays in vitro and in vivo. Furthermore, molecular mechanism of DEPDC1B in chordoma cells was recognized by RNA sequencing and Co-Immunoprecipitation (Co-IP) assay. The malignant behaviors of DEPDC1B knockdown chordoma cells was significantly inhibited, which was characterized by reduced proliferation, enhanced apoptosis, and hindered migration. Consistently, decreased expression of DEPDC1B suppressed tumor growth in xenograft mice. Mechanically, DEPDC1B affected the ubiquitination of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) through ubiquitin-conjugating enzyme E2T (UBE2T). Simultaneous downregulation of BIRC5 and DEPDC1B may exacerbate the inhibitory effects of chordoma. Moreover, BIRC5 overexpression reduced the inhibitory effects of DEPDC1B knockdown in chordoma cells. In conclusion, DEPDC1B regulates the progression of human chordoma through UBE2T-mediated ubiquitination of BIRC5, suggesting that it may be a promising candidate target with potential therapeutic value.
脊索瘤是一种罕见的骨恶性肿瘤，具有很高的局部复发率和远处转移率。虽然 DEP 结构域包含蛋白 1B（DEPDC1B）与多种恶性肿瘤有关，但它与脊索瘤的关系尚不清楚。在这项研究中，探讨了 DEPDC1B 在脊索瘤中的生物学作用和分子机制。通过体外和体内的功能丧失实验，阐明了 DEPDC1B 在脊索瘤细胞中的功能。此外，通过 RNA 测序和 Co-Immunoprecipitation（Co-IP）实验，鉴定了 DEPDC1B 在脊索瘤细胞中的分子机制。DEPDC1B 敲低的脊索瘤细胞的恶性行为明显受到抑制，表现为增殖减少、凋亡增强和迁移受阻。同样，DEPDC1B 表达下调抑制了异种移植小鼠的肿瘤生长。在机制上，DEPDC1B 通过泛素连接酶 E2T（UBE2T）影响杆状病毒凋亡抑制重复包含蛋白 5（BIRC5）的泛素化。同时下调 BIRC5 和 DEPDC1B 可能会加剧脊索瘤的抑制作用。此外，BIRC5 的过表达减少了 DEPDC1B 敲低对脊索瘤细胞的抑制作用。总之，DEPDC1B 通过 UBE2T 介导的 BIRC5 泛素化调节人脊索瘤的进展，表明它可能是一种有前途的候选治疗靶点，具有潜在的治疗价值。
