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Nuclear and cytosolic fractions of SOX2 synergise as transcriptional and translational co-regulators of cell fate

ABSTRACT: Stemness depends on a series of specific transcription regulators that suppress default differentiation and/or promote self-renewal. A prominent example thereof is SOX2 (SRY homology Box 2), a protein that further contributes to pluripotency and the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Here we uncover that SOX2 exerts these functions not only via transcriptional roles, but also by directly regulating translation. We show that SOX2 associates with ribosomal 40S subunits in the cytoplasm to alter the protein expression of signaling factors and metabolic components pivotal for stemness. Specifically, a low complexity region in the C-terminal part of SOX2 that interacts with the ribosome to modulate protein synthesis, is identified as critically required for SOX2-induced clonogenicity in human cancer cells and the reprogramming of fibroblasts to iPSCs. Mechanistically, SOX2 translationally enforces insulin/PI3K signaling while suppressing the formation of acetyl CoA synthetase 2 (ACSS2) protein, a driver of acetate consuming cell differentiation. Expression of either full-length SOX2 or its C-terminus only increases glucose consumption and acidification in cultured human cancer cells, thereby promoting clonogenicity. In the absence of SOX2 expression, ACSS2 knockdown or supplementation with acetate provide a partial rescue. Together, these data indicate novel ribosome-based mechanistic contributions of pluripotency factors to stemness and cell fate determination.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Thomas Bock

LAB HEAD: Alexander Schmidt

PROVIDER: PXD015157 | Pride | 2024-09-16

REPOSITORIES: Pride

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Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile Sox2-GFP expressing CSC to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Two different biological replicates from SOX2-GFP+ and SOX2-GFP- TECs (control) from 2 different SCC from 2 different mice were analysed. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.

Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile tumour epithelial cells upon Sox2 deletion to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Microarray analysis was performed on FACS isolated Epcam+ a6+ TECs from 3 different biological experiments following TAM administration to K14CREER:SOX2fl/fl and control mice. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.

			Action	DRS
	001_EXP5_C1_A17.raw	Raw
	001_SC-PILOT.raw	Raw
	001r_OVCar2_A17.raw	Raw
	002_EXP5_C2_A17.raw	Raw
	002_SC-PILOT.raw	Raw

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Nuclear and cytosolic fractions of SOX2 synergise as transcriptional and translational co-regulators of cell fate

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