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Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE112703 | GEO | 2018/12/13

REPOSITORIES: GEO

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Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [microarray]

Project description:SUFU alterations are commonly detected in human SHH subgroup of medulloblastoma. Here we profile the gene expression of P13 wildtype and Sufu KO cerebellum, as well as Ptch1 KO MB in biological triplicate.

2018-12-13 | GSE112699 | GEO

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [RNA-seq]

Project description:GLI2 overexpression is a hallmark in SHH subgroup of medulloblastoma (SHH MB). Here we profile the transcriptome of two mouse models of SHH MB expressing high Gli2: SmoM2 overexpression and Sufu;Spop double knockout MB.

2018-12-13 | GSE112772 | GEO

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [ChIP-seq]

Project description:GLI2 overexpression is a hallmark in SHH subgroup of medulloblastoma (SHH MB). Here we identify the targetome of Gli2 in two mouse models of SHH MB: SmoM2 overexpression and Sufu;Spop double knockout MB.

2018-12-13 | GSE112702 | GEO

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability

Project description:Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability

| PRJNA448760 | ENA

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [microarray]

Project description:Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [microarray]

| PRJNA448762 | ENA

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [RNA-seq]

Project description:Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [RNA-seq]

| PRJNA448928 | ENA

Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [ChIP-seq]

Project description:Sufu and Spop cooperate to suppress SHH medulloblastoma tumorigenesis via regulation of Gli2 protein stability [ChIP-seq]

| PRJNA448761 | ENA

SPOP-PTEN-SUFU axis promotes progression of clear cell renal cell carcinoma via activating SHH and WNT pathway.

Project description: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.

| S-EPMC8140158 | biostudies-literature

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis.

Project description:Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis.

| S-EPMC5841288 | biostudies-literature

Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors.

Project description:Gli2 and Gli3 are primary transcriptional regulators that mediate hedgehog (Hh) signaling. Mechanisms that stabilize and destabilize Gli2 and Gli3 are essential for the proteins to promptly respond to Hh signaling or to be inactivated following the activation. In this study, we show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. By contrast, RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins, but not those of their repressors, whereas introducing Sufu into the MEFs stabilizes Gli2 and Gli3 full-length proteins and rescues Gli3 processing. Consistent with these findings, forced Spop expression promotes Gli2 and Gli3 degradation and Gli3 processing. The functions of Sufu and Spop oppose each other through their competitive binding to the N- and C-terminal regions of Gli3 or the C-terminal region of Gli2. More importantly, the Gli3 repressor expressed by a Gli3 mutant allele (Gli3(Delta699)) can mostly rescue the ventralized neural tube phenotypes of Sufu mutant embryos, indicating that the Gli3 repressor can function independently of Sufu. Our study provides a new insight into the regulation of Gli2 and Gli3 stability and processing by Sufu and Spop, and reveals the unexpected Sufu-independent Gli3 repressor function.

| S-EPMC2875842 | biostudies-other

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