Targeting the anaphase-promoting complex/cyclosome (APC/C)- bromodomain containing 7 (BRD7) pathway for human osteosarcoma.
Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence and has a propensity for local invasion and early lung metastasis. However, the current therapies often result in chemoresistance, and a therapeutic target is not available in the clinic for osteosarcoma. Here, we report that BRD7 forms a complex with the anaphase-promoting complex/cyclosome (APC/C) and is degraded by APC/C(cdh1) and APC/C(cdc20) during the cell cycle. Moreover, BRD7 is a tumor suppressor in osteosarcoma, and the BRD7 mutant resistant to degradation by APC/C is more efficient than the wild-type protein at suppressing proliferation, colony formation, and tumor growth of osteosarcoma in vitro and in vivo. The combination of proTAME, an inhibitor of APC/C, with chemotherapeutic drugs efficiently targets osteosarcoma in vitro. Furthermore, there is a strong inverse correlation of protein levels between BRD7 and Cdh1 or Cdc20, and lower BRD7 expression is an indicator for poor prognosis in patients with osteosarcoma. Collectively, our results indicate that targeting the APC/C-BRD7 pathway may be a novel strategy for treating osteosarcoma.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Kaishun
K
Hu
Dan
D
Liao
Wenjing
W
Wu
An-Jia
AJ
Han
Hui-Juan
HJ
Shi
Fen
F
Wang
Xin
X
Wang
Li
L
Zhong
Tingmei
T
Duan
Yuanzhong
Y
Wu
Jingying
J
Cao
Jianjun
J
Tang
Yi
Y
Sang
Li
L
Wang
Xiaobin
X
Lv
Shuangbing
S
Xu
Ru-Hua
RH
Zhang
Wu-Guo
WG
Deng
Sheng-Ping
SP
Li
Yi-Xin
YX
Zeng
Tiebang
T
Kang
D000293:Adolescent; D000328:Adult; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
D064173:Anaphase-Promoting Complex-Cyclosome; D002868:Chromosomal Proteins, Non-Histone; D034741:RNA, Small Interfering; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins