SOX1 promotes differentiation of nasopharyngeal carcinoma cells by activating retinoid metabolic pathway

Abstract

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seqprofiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

SOX1 acts as a tumor hypnotist rendering nasopharyngeal carcinoma cells refractory to chemotherapy

“…SOX1 might recruit transcriptional repressors to halt the expression of MYC. In addition, we mutated two amino acids (Arg53 to Asp and Asn78 to Ala) in HMG domain to destroy the transcriptional function of SOX1, which was veri ed by our previous work [11]. Following the experimental model mimicking QCCs, the mutant form couldn't induce QCCs and clustered colonies didn't arise (Fig.…”

“…The plasmids encoding human SOX1 and its mutant were generated by PCR ampli cation and subcloned into the pLVX-TRE3G expression vector using the ClonExpress II One Step Cloning Kit or ClonExpress MultiS One Step Cloning Kit (Vazyme, C112-02 or C113-02) according to the manufacturer's instructions, which was named "pLVX-TRE-SOX1". The primers used for gene cloning are listed in our previous work [11].…”

“…Stable clones (HONE1 TRE-SOX1 and CNE2 TRE-SOX1) were established in our previous work [11] and overexpression of SOX1 was induced by doxycycline treatment under the Tet-ON system. Principal component analysis (PCA) analysis showed that within-group distributions of gene expression pro les were well clustered (Supplementary Fig.…”

SOX14 hypermethylation as a tumour biomarker in cervical cancer

“…SOX14 is a member of the SOX gene family, which mediates the binding of high-mobility group (HMG) domains to DNA and has regulatory functions in development, the cell cycle and differentiation [ 9 ]. Previous studies have discovered that many genes in the SOX family participate in carcinogenesis, such as SOX1, which can affect the growth and invasion of cancer cells in cervical cancer [ 10 ], breast cancer [ 11 ], lung cancer [ 12 ], glioblastoma [ 13 ] and nasopharyngeal cancer [ 14 ]. SOX2, SOX6 and SOX17 are associated with the occurrence of sarcomas [ 15 ].…”

Expression and significance of SOX B1 genes in glioblastoma multiforme patients

“…Accumulating evidence suggests that SOX B1 genes have both antiproliferative and prosurvival effects, depending on cancer. On the one hand, SOX B1 members have been shown to be tumour suppressors in nasopharyngeal carcinoma, 10 ovarian cancer 11 and metrocarcinoma. 12 , 13 On the other hand, SOX B1 genes have been shown to play an oncogenic role in breast cancer, 14 , 15 squamous cell carcinoma, 16 hepatocellular carcinoma, 17 osteosarcoma 18 , 19 and brain cancer.…”