USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Anan Li; Shijiang Wang; Jiangbo Nie; Shining Xiao; Xinsheng Xie; Yu Zhang; Weilai Tong; Geliang Yao; Ning Liu; Fan Dan; Zhiguo Shu; Jiaming Liu; Zhili Liu; Feng Yang

doi:10.1038/s41419-024-06624-7

USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Cell Death Dis. 2024 Mar 26;15(3):235. doi: 10.1038/s41419-024-06624-7.

Authors

Anan Li^#^{1

2

3}, Shijiang Wang^#^{1

2

3}, Jiangbo Nie^{1

2

3}, Shining Xiao^{1

2

3}, Xinsheng Xie^{2

3}, Yu Zhang^{1

2

3}, Weilai Tong^{1

2

3}, Geliang Yao^{1

2

3}, Ning Liu^{1

2

3}, Fan Dan^{1

2

3}, Zhiguo Shu^{1

2

3}, Jiaming Liu^{1

2

3}, Zhili Liu^{4

5

6}, Feng Yang^{7

8

9

10}

Affiliations

¹ Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
² Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
³ Institute of Spine and Spinal Cord, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
⁴ Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. zhili-liu@ncu.edu.cn.
⁵ Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. zhili-liu@ncu.edu.cn.
⁶ Institute of Spine and Spinal Cord, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. zhili-liu@ncu.edu.cn.
⁷ Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. feng_yang@ncu.edu.cn.
⁸ Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. feng_yang@ncu.edu.cn.
⁹ Institute of Spine and Spinal Cord, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. feng_yang@ncu.edu.cn.
¹⁰ Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. feng_yang@ncu.edu.cn.

^# Contributed equally.

Abstract

Ubiquitin-specific protease 3 (USP3) plays an important role in the progression of various tumors. However, the role of USP3 in osteosarcoma (OS) remains poorly understood. The aim of this study was to explore the biological function of USP3 in OS and the underlying molecular mechanism. We found that OS had higher USP3 expression compared with that of normal bone tissue, and high expression of USP3 was associated with poor prognosis in patients with OS. Overexpression of USP3 significantly increased OS cell proliferation, migration, and invasion. Mechanistically, USP3 led to the activation of the PI3K/AKT signaling pathway in OS by binding to EPHA2 and then reducing its protein degradation. Notably, the truncation mutant USP3-F2 (159-520) interacted with EPHA2, and amino acid 203 was found to play an important role in this process. And knockdown of EPHA2 expression reversed the pro-tumour effects of USP3-upregulating. Thus, our study indicates the USP3/EPHA2 axis may be a novel potential target for OS treatment.

MeSH terms

Bone Neoplasms* / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Humans
Osteosarcoma* / pathology
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Ubiquitin-Specific Proteases / metabolism

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
USP3 protein, human
Ubiquitin-Specific Proteases

Abstract

MeSH terms

Substances

Grants and funding