SOX2-dependent expression of dihydroorotate dehydrogenase regulates oral squamous cell carcinoma cell proliferation

Oral squamous cell carcinoma(OSCC)become a heavy burden of public health,with approximately 300000 newly diagnosed cases and 145000 deaths worldwide per year.Nucleotide metabolism fuel DNA replication and RNA synthesis,which is indispensable for cell proliferation.But how tumor cells orchestrate nucleotide metabolic enzymes to support their rapid growth is largely unknown.Here we show that expression of pyrimidine metabolic enzyme dihydroorotate dehydrogenase(DHODH)is upregulated in OSCC tissues,compared to non-cancerous adjacent tissues.Enhanced expression of DHODH is correlated with a shortened patient survival time.Inhibition of DHODH by either shRNA or selective inhibitors impairs proliferation of OSCC cells and growth of tumor xenograft.Further,loss of functional DHODH imped de novo pyrimidine synthesis,and disrupt mitochondrial respiration probably through destabilizing the MICOS complex.Mechanistic study shows that transcriptional factor SOX2 plays an important role in the upregulation of DHODH in OSCC.Our findings add to the knowledge of how cancer cells co-opt nucleotide metabolism to support their rapid growth,and thereby highlight DHODH as a potential prognostic and therapeutic target for OSCC treatment.

FGF8 induces epithelial-mesenchymal transition and promotes metastasis in oral squamous cell carcinoma

Oral squamous cell carcinoma(OSCC)is one of the most common cancers worldwide,and with 354864 new cases each year.Cancer metastasis,recurrence,and drug resistance are the main causes to cripples and deaths of OSCC patients.As potent growth factors,fibroblast growth factors(FGFs)are frequently susceptible to being hijacked by cancer cells.In this study,we show that FGF8 is upregulated in OSCC tissues and high FGF8 expression is related with a set of clinicopathologic parameters,including age,drinking,and survival time.FGF8 treatment enhances the invasive capability of OSCC cells.Lentivirus-based FGF8 expression promotes OSCC metastasis in a mouse lung metastasis model.Further,mechanistic study demonstrates that FGF8 induces epithelial–mesenchymal transition(EMT)in OSCC cells.These results highlight a pro-metastatic function of FGF8,and underscore the role of FGF8 in OSCC development.

RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA repair

Exposure to radiation causes DNA damage;hence, continuous surveillance and timely DNA repair are important for genome stability. Epigenetic modifications alter the chromatin architecture, thereby affecting the efficiency of DNA repair. However, how epigenetic modifiers coordinate with the DNA repair machinery to modulate cellular radiosensitivity is relatively unknown. Here, we report that loss of the demethylase ribosomal oxygenase 1(RIOX1) restores cell proliferation and reduces cell death after exposure to ionizing radiation. Furthermore, RIOX1 depletion enhances homologous recombination(HR) repair but not nonhomologous endjoining(NHEJ) repair in irradiated bone marrow cells and oral mucosal epithelial cells. Mechanistic study demonstrates that RIOX1 removes monomethylation at K491 of cyclic GMP-AMP synthase(c GAS) to release c GAS from its interaction with the methyl-lysine reader protein SAGA complex-associated factor 29(SGF29), which subsequently enables c GAS to interact with poly(ADP-ribosyl)ated poly(ADP-ribose) polymerase 1(PARP1) at DNA break sites, thereby blocking PARP1-mediated recruitment of Timeless. High expression of RIOX1 maintains c GAS K491 me at a low level, which impedes HR repair and reduces cellular tolerance to ionizing radiation. This study highlights a novel RIOX1-dependent mechanism involved in the non-immune function of c GAS that is essential for the regulation of ionizing radiation-elicited HR repair.