SPOP\u2013PTEN\u2013SUFU axis promotes progression of clear cell renal cell carcinoma via activating SHH and WNT pathway

Bo’Ang Han,Yu Wang,Lun Kuang,Shen Yue,Tianyuan Li,Jing Cai,Chen Liu,Yuan Xu,Steven Y Cheng,Zhen Sun,Tingting Yu,Binbin Gao,Qing Cao

doi:10.1038/s41420-021-00484-2

Abstract

Although E3 ligase Speckle type BTB/POZ protein (SPOP) promotes tumorigenesis by acting as a key regulatory hub in clear cell renal cell carcinoma (ccRCC), the detailed molecular mechanism remains unclear. Here, we demonstrate that a well-known tumor suppressor, Suppressor of Fused (SUFU), is downregulated by SPOP. Interestingly, this downregulation depends on cullin-3(Cul3)-SPOP E3 ligase, but SUFU is not a direct substrate of SPOP. Phosphatase and tensin homolog (PTEN), a ubiquitinated substrate of SPOP, is involved in SPOP-mediated SUFU reduction. Importantly, inhibition of SUFU leads to elevated SHH and WNT signaling, consequently rescuing the reduced proliferation, migration, and invasion abilities of ccRCC cells caused by SPOP-knockdown. Moreover, combinatorial treatment with SHH and WNT inhibitors shows more effective for suppressing ccRCC cell proliferation and aggressiveness. These findings demonstrate that a novel SPOP–PTEN–SUFU axis promotes ccRCC carcinogenesis by activating SHH and WNT pathway, providing a new treatment strategy for ccRCC.

Highlights

Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system
speckle type BTB/POZ protein (SPOP) downregulates Suppressor of Fused (SUFU) in mammals Our previous study reported that SUFU is downregulated by Hedgehog-induced BTB protein (HIB)/SPOP in Drosophila, so we further evaluated whether SUFU can be suppressed by SPOP in mammalian system[9]
To exclude the possibility that the reduction was due to transcriptional downregulation, we performed quantitative real-time PCR to measure the mRNA levels of SUFU in SPOP-overexpressing cells

Summary

Introduction

Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system. Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of RCC, accounting for ~75% of all cases[2]. Metastatic RCC is usually difficult to cure, The ubiquitin E3 ligase speckle type BTB/POZ protein (SPOP), acting as a key regulatory hub in kidney cancer, has been reported to promote ccRCC tumorigenesis and progression through ubiquitinating and degrading several tumor suppressors[4,5]. Overexpressed SPOP in ccRCC cells promotes proliferation and inhibits apoptosis through the ubiquitin–proteasome-mediated degradation of phosphatase and tensin homolog (PTEN), dual-specificity phosphatase 7 (DUSP7), death domain-associated protein (DAXX), and Sonic hedgehog (SHH) transcription factor glioma-associated oncogene homolog 2 (GLI2). SPOP promotes the tumor invasiveness by degrading large tumor suppressor 1(LAST1) or enhancing the transcription factor β-catenin protein expression, as Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion