SAPCD2 promotes neuroblastoma progression by altering the subcellular distribution of E2F7

Zi-Mu Zhang,Si-Qi Jia,Haibo Cao ,Di Wu,Jinfang Yu ,Yang Yang,Jianwei Wang ,Yunyun Xu ,Chen-Xi Feng,Xinyi Guo ,Fang Fang,Yi Xie,Yanling Chen ,Randong Yang ,Zhiheng Li ,Xiaolu Li ,Guanghui Qian ,Gen Li,Ran Zhuo,Yan-Fang Tao,Hairong Wang ,Xinmei Liao ,Jian Pan

doi:10.1038/s41419-022-04624-z

Zi-Mu Zhang, Si-Qi Jia + Show 21 more

Open Access

https://doi.org/10.1038/s41419-022-04624-z

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Abstract

Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.

Highlights

Neuroblastoma (NB) is one of the most common malignant extracranial solid tumors in pediatric patients that originates from neural crest cells of the sympathetic nervous system and accounts for up to 15% of cancer-related mortality in children [1]
SAPCD2 is associated with the NB progression GSK-J4 is a small-molecule inhibitor of lysine 27 of histone 3 (H3K27) demethylases and has been shown to have anti-NB efficacy in a range of NB cell lines
Compared to the control group, we identified 19 downregulated genes shared by distinct NB cell lines treated with GSK-J4

Summary

INTRODUCTION

Neuroblastoma (NB) is one of the most common malignant extracranial solid tumors in pediatric patients that originates from neural crest cells of the sympathetic nervous system and accounts for up to 15% of cancer-related mortality in children [1]. With the aim to discover new players involved in the progression of NB, we performed bioinformatics analysis of the GSK-J4 regulatory network and identified 19 genes that are significantly downregulated in multiple GSK-J4-treated NB cell lines. Among those genes, SAPCD2 (suppressor anaphasepromoting complex domain containing 2) emerged as an appealing target for further investigations given its high connection to poor patient prognosis and in consideration of the lack of understanding of its roles and regulatory mechanisms in NB. Data were representative of three independent experiments in B. analysis revealed that SAPCD2-knockdown limited E2F signaling activation in NB cells affected the expression of genes involved in the cell cycle and chromosome instability. Our study provided evidences of a previously unrecognized role of SAPCD2 in the E2F signaling pathway and revealed a novel target and potential therapeutic strategy for clinical NB treatment

RESULTS

DISCUSSION

CONFLICT OF INTEREST