Small-Molecule Inhibitors of the SOX18 Transcription Factor

Fontaine, Frank; Overman, Jeroen; Moustaqil, Mehdi; Mamidyala, Sreeman K.; Salim, Angela A.; Narasimhan, Kamesh; Prokoph, Nina; Robertson, Avril A. B.; Lua, Linda H.L.; Alexandrov, Kirill; Koopman, Peter; Capon, Robert J.; Sierecki, Emma; Gambin, Yann; Jauch, Ralf; Cooper, Matthew A.; Zuegg, Johannes; François, Mathias

doi:10.1016/j.chembiol.2017.01.003

Cited by 42 publications

(53 citation statements)

References 64 publications

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“…SOX18 homo- and heterodimerization can be inhibited by a small molecule, SM4 20–22 and by an FDA-approved beta blocker, propranolol 23 . Propranolol is produced as a 1:1 racemic mixture of R(+) and S(-) enantiomers.…”

Section: Resultsmentioning

confidence: 99%

“…It has so far been linked to the transcriptional regulation of ECs and to the progression of solid cancers 34, 35 . SOX18 forms a dimer 20, 21 , able to bind to the viral and cellular genomes. This may lead to a stronger viral episome tethering to the host genome, thus improving the efficiency of KSHV genome retention.…”

Section: Discussionmentioning

confidence: 99%

“…PROX1 WT and PROX1 MUT expressing lentiviruses were described previously 20 . The control pFuW-myc-NLS-mCherry was generated from the pFuW-myc-BirA-NLS-mCherry (a kind gift by R.Kivela, University of Helsinki).…”

Section: Methodsmentioning

confidence: 99%

“…PAA (Cat#284270); R-Propranolol (Cat#P0689), S-Propranolol (Cat#P8688) and R-S Propanolol (Cat#P0884) were obtained from Sigma-Aldrich; Sm4 was kindly provided by M. Francois 20 .…”

Section: Methodsmentioning

confidence: 99%

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Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

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27Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection 28 and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency 29 in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with 30 high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, 31 SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique 32 KSHV infection program. We found that these factors were co-expressed in KS tumours with the 33 viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent 34 mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition 35 significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator 36 of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces 37 KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in 38 the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate 39 the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and 40 introduce SOX18 inhibition as a potential, novel therapeutic modality for KS. 41 42 43 KEYWORDS 44 Kaposi sarcoma, KSHV, herpesvirus, K8.1, transcription factors, PROX1, SOX18, lymphatic 45 endothelial cells, viral genome replication, viral reactivation. 46 47 3 MAIN 48Kaposi sarcoma (KS) is an angiogenic endothelial tumour caused by KS herpesvirus (KSHV). KS is 49 the most common cancer among AIDS patients and a frequent malignancy in Sub-Saharan Africa 1 . 50 KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; 51 in advanced disease visceral involvement is also seen 2,3 . The histopathological hallmark of KS is the 52 presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2,3 . The cell of origin of SC has 53 been debated for two decades 3 . The prevailing hypothesis suggests lymphatic endothelial origin, 54 although blood endothelial cells or mesenchymal cells are also candidates 1,4 . In vitro, latency is the 55 default replication program in KSHV-infected cells with undetectable levels of lytic genes expressed. 56 However, KSHV infection of lymphatic, but not blood, endothelial cells (LEC and BEC) leads to a 57 unique infection program characterized by high KSHV genome copies, spontaneous lytic gene 58 expression and release of infectious virus 5-8 . 59 60 During embryonic development, LEC precursors originate from COUPTF2/SOX18 double-positive 61 BECs that physically separate from the cardinal vein to establish a primary lymphatic vascular plexus. 62 In this process, COUPTF2 and SOX18 drive the expression of PROX1 thereby orchestrating LEC 63 differentiation 9,10 . Here, we explored the role of these transcription factors (TF), instrumental for 64 establishment...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…PAA (Cat#284270); R-Propranolol (Cat#P0689), S-Propranolol (Cat#P8688) and R-S Propanolol (Cat#P0884) were obtained from Sigma-Aldrich; Sm4 was kindly provided by M. Francois 20 .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

Self Cite

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“…The SOX family is composed of a class of transcription factors that contain highly conserved HMG DNA binding domains . The most significant biological function of SOX is related to the determination and differentiation of specific cell lines during embryonic development.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous expression and biological function of SOX18 in osteosaroma

Zhu

Yang

et al. 2018

J of Cellular Biochemistry

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Osteosaroma (OS) is a primary bone malignancy and is associated with high morbidity. Sex determining region Y-box 18 (SOX18) is identified overexpressed in OS. However, the molecular mechanism underlying the biological function of SOX18 in OS is still unclear. The aim of the current study was to determine the SOX18 expression in patients with OS and its effect on tumor cell malignant phenotypes. Our results showed that SOX18 was overexpressed in OS patients from both E-MEXP-3628 database and independent samples from our hospital and in OS cell lines. SOX18 silencing significantly induced G0-G1 phase cell cycle arrest and apoptosis and inhibited U-2OS cell migration and invasion and cell growth both in vitro and in vivo. However, SOX18 overexpression remarkably promoted 143B cell proliferation, migration and invasion and inhibited cell cycle arrest and apoptosis. The protein expression levels of p53, p21, Bax, Bcl-2, and Caspase-3 were also regulated by SOX18. Moreover, SOX18 was found negative correlated with the expression of HERC1, HER2, HERC3, HERC4, HERC5, and HERC6 in OS patients and in OS cells, with the most significant correlation detected in HERC2 expression, which was following found interacted with SOX18 in OS cells. Taken together, our results suggest that SOX18 is overexpressed in OS and plays an important role in proliferation, apoptosis, migration and invasion of OS cells, and may provide a novel and promising thera-peutic strategy for OS.

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Transplanting Human Neural Stem Cells with ≈50% Reduction of SOX9 Gene Dosage Promotes Tissue Repair and Functional Recovery from Severe Spinal Cord Injury

et al. 2023

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Neural stem cells (NSCs) derived from human pluripotent stem cells (hPSCs) are considered a major cell source for reconstructing damaged neural circuitry and enabling axonal regeneration. However, the microenvironment at the site of spinal cord injury (SCI) and inadequate intrinsic factors limit the therapeutic potential of transplanted NSCs. Here, it is shown that half dose of SOX9 in hPSCs-derived NSCs (hNSCs) results in robust neuronal differentiation bias toward motor neuron lineage. The enhanced neurogenic potency is partly attributed to the reduction of glycolysis. These neurogenic and metabolic properties retain after transplantation of hNSCs with reduced SOX9 expression in a contusive SCI rat model without the need for growth factor-enriched matrices. Importantly, the grafts exhibit excellent integration properties, predominantly differentiate into motor neurons, reduce glial scar matrix accumulation to facilitate long-distance axon growth and neuronal connectivity with the host as well as dramatically improve locomotor and somatosensory function in recipient animals. These results demonstrate that hNSCs with half SOX9 gene dosage can overcome extrinsic and intrinsic barriers, representing a powerful therapeutic potential for transplantation treatments for SCI.

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Small-Molecule Inhibitors of the SOX18 Transcription Factor

Cited by 42 publications

References 64 publications

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Heterogeneous expression and biological function of SOX18 in osteosaroma

Transplanting Human Neural Stem Cells with ≈50% Reduction of SOX9 Gene Dosage Promotes Tissue Repair and Functional Recovery from Severe Spinal Cord Injury

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