A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity

Xujia Wu,Xixi Li,Huangkai Zhou,Maolei Zhang,Feizhe Xiao,Xuesong Yang,Songhua Xiao,Jian Zhong,Nunu Huang,Nu Zhang,Fanying Li,Dawei Liu,Lixuan Yang,Xin Xia,Bo Li

doi:10.1186/s13059-020-02250-6

Abstract

BackgroundAberrant activation of the Hedgehog pathway drives tumorigenesis of many cancers, including glioblastoma. However, the sensitization mechanism of the G protein-coupled-like receptor smoothened (SMO), a key component of Hedgehog signaling, remains largely unknown.ResultsIn this study, we describe a novel protein SMO-193a.a. that is essential for Hedgehog signaling activation in glioblastoma. Encoded by circular SMO (circ-SMO), SMO-193a.a. is required for sonic hedgehog (Shh) induced SMO activation, via interacting with SMO, enhancing SMO cholesterol modification, and releasing SMO from the inhibition of patched transmembrane receptors. Deprivation of SMO-193a.a. in brain cancer stem cells attenuates Hedgehog signaling intensity and suppresses self-renewal, proliferation in vitro, and tumorigenicity in vivo. Moreover, circ-SMO/SMO-193a.a. is positively regulated by FUS, a direct transcriptional target of Gli1. Shh/Gli1/FUS/SMO-193a.a. form a positive feedback loop to sustain Hedgehog signaling activation in glioblastoma. Clinically, SMO-193a.a. is more specifically expressed in glioblastoma than SMO and is relevant to Gli1 expression. Higher expression of SMO-193a.a. predicts worse overall survival of glioblastoma patients, indicating its prognostic value.ConclusionsOur study reveals that SMO-193a.a., a novel protein encoded by circular SMO, is critical for Hedgehog signaling, drives glioblastoma tumorigenesis and is a novel target for glioblastoma treatment.

Highlights

Aberrant activation of the Hedgehog pathway drives tumorigenesis of many cancers, including glioblastoma
Circ-SMO expression is enriched in cancer stem cells (CSCs) and GBM To identify differential HH signaling status in glioma, we enrolled a panel of different brain tumor cells including SW1783, HS683, U118, U373 (GBM lines), and 387, 4121, 456, and 3691(CSC lines)
We found that HH signaling was considerably higher activated in CSCs compared with that in glioma cell lines and normal control cells (Fig. 1a)

Summary

Introduction

Aberrant activation of the Hedgehog pathway drives tumorigenesis of many cancers, including glioblastoma. The sensitization mechanism of the G protein-coupled-like receptor smoothened (SMO), a key component of Hedgehog signaling, remains largely unknown. As a key regulator for fate determination of embryonic stem cells but quiescent in adult cells, aberrant HH pathway activation was frequently observed in many human cancers such as medulloblastoma, basal cell carcinoma (BCC), and GBM [1,2,3]. The detail mechanism of releasing SMO from PTCH inhibition, which is the key to understand HH signaling, remains largely unknown [6]. Previous study demonstrated that HH signaling activation was present in a subset of GBM tumors, and SMO inhibition was effective in glioma lines highly expressing Gli, indicating HH signaling is likely to be a driver in a subset of GBMs [13]. Vismodegib, a SMO-specific inhibitor, is a promising therapeutic approach for cancer treatment in BCC and medulloblastoma [15, 16], but the effectiveness remains to be determined in GBM [17]

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Discussion

Conclusion