DEPDC1B regulates the progression of human chordoma through UBE2T-mediated ubiquitination of BIRC5

Liang Wang,Xiaodong Zhu,Junpeng Ma,Kaibing Tian,Yanghu Lu,Ruijun Xu,Zhen Wu,Yanbin Liu,Liang Tang

doi:10.1038/s41419-021-04026-7

Abstract

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.

Highlights

Chordoma is a rare, slow-growing primary bone malignancy that originates from primitive notochordal tissue [1, 2]
Knockdown of DEP domain-containing protein 1B (DEPDC1B) inhibits the malignant behaviors of chordoma cells in vitro First of all, Western blotting (WB) results showed that the protein level of DEPDC1B was highly expressed in U-CH1 and MUG-Chor1 cells (Fig. S1A)
Knockdown of DEPDC1B inhibits the malignant behavior of chordoma cells in vitro, such as reduction of proliferation, induction of apoptosis, and inhibition of migration

Summary

Introduction

Slow-growing primary bone malignancy that originates from primitive notochordal tissue [1, 2]. Chordomas do not respond to conventional radiotherapy or cytotoxic chemotherapy, and surgery is the primary treatment option [4, 5]. Traditional treatment options are far from adequate [6]. The nuclear expression of brachyury, a key transcription factor for notochord development, can be used as a classic diagnostic marker for chordoma [7, 8]. A variety of potential molecular targets for chordoma were identified, such as platelet-derived growth factor receptor β, PI3K/mTOR, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and tyrosine kinase. Identification of new potential molecular targets is essential for patients with chordoma

Methods

Results

Conclusion