J Cancer 2021; 12(6):1826-1837. doi:10.7150/jca.52115

Research Paper

Overexpression of HIPK2 removes the transrepression of proapoptotic genes mediated by the CtBP1-p300-FOXO3a complex and increases the chemosensitivity in osteosarcoma cells

Ning Duan1,2#, Wentao Zhang2#, Zhong Li2, Liang Sun2, Tao Song2, Zirui Yu2, Xun Chen2✉, Wei Ma1✉

1. Department of Orthopedics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
2. Department of Orthopedic Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China.
#These authors contributed equally to this work.

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Citation:
Duan N, Zhang W, Li Z, Sun L, Song T, Yu Z, Chen X, Ma W. Overexpression of HIPK2 removes the transrepression of proapoptotic genes mediated by the CtBP1-p300-FOXO3a complex and increases the chemosensitivity in osteosarcoma cells. J Cancer 2021; 12(6):1826-1837. doi:10.7150/jca.52115. Available from https://www.jcancer.org/v12p1826.htm

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Abstract

Decreased expression of proapoptotic genes can lead to the chemoresistenance in cancer therapy. Carboxyl-terminal binding protein 1 (CtBP1), a transcriptional corepressor with multiple oncogenic effects, has been previously identified to suppress the expression of two proapoptotic genes [BAX (BCL2 associated X) and BIM (Bcl-2 interacting mediator of cell death)] by assembling a complex with the Forkhead box O3 (FOXO3a) transcription factor and the p300 histone acetyltransferase. However, the upstream regulatory signaling of the CtBP1-p300-FOXO3a complex is obscure, and the effects of changing this signaling on chemosensitivity in osteosarcoma are unknown. Herein, we discovered that the downregulation of HIPK2 (Homeodomain-interacting protein kinase 2) was essential for the function of the CtBP1-p300-FOXO3a complex. Downregulation of HIPK2 prevented the phosphorylation and subsequent degradation of CtBP1, thereby allowing the assembly of the CtBP1-p300-FOXO3a complex and suppression of the expression of proapoptotic genes, such as BAX, BIM, BIK (Bcl-2 interacting killer) and NOXA/PMAIP1 (Phorbol-12-myristate-13-acetate-induced protein 1). Overexpression of HIPK2 promoted the phosphorylation of CtBP1 and the degradation of CtBP1 by proteasomes, thereby preventing the formation of the CtBP1-p300-FOXO3a complex. The abolition of CtBP1 transrepression increased the expression of proapoptotic genes to induce apoptosis and increase chemosensitivity in osteosarcoma cells. Taken together, our in vitro and in vivo results revealed that overexpression of HIPK2 could remove the CtBP1-mediated transrepression of proapoptotic genes, indicating a new therapeutic option for the treatment of osteosarcoma.

Keywords: CtBP1, HIPK2, proapoptotic genes, chemosensitivity, osteosarcoma