Abstract
SummaryOral squamous cell carcinoma (OSCC) become a heavy burden of public health, with approximately 300 000 newly diagnosed cases and 145 000 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.
Highlights
Head and neck cancer squamous cell carcinoma (HNSCC) ranks as the sixth-most common cancer worldwide, with an annual incidence of greater than 650 000 cases and causing 350 000 deaths annually.[1]
Inhibition of dihydroorotate dehydrogenase (DHODH) impeded Oral squamous cell carcinoma (OSCC) cell proliferation To explore the role of DHODH in OSCC development, we examined the impact of DHODH expression on OSCC cell proliferation
Inhibition of DHODH impairs pyrimidine nucleotide synthesis Considering that cancer cells frequently hijack nucleotide metabolism to boost cell proliferation,[14] we examined the role of DHODH in cellular de novo pyrimidine synthesis in OSCC cells
Summary
Xuemei Qiu 1, Sheng Jiang[2], Yanxuan Xiao[1], Yumin He1, Tao Ren[3], Lu Jiang[1], Rui Liu 1 and Qianming Chen[1]. 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. Orotate is attached to the ribose-5-phosphate ring to form orotidine 5′-monophosphate (OMP), which is the precursor to generate cytosine, thymine, or uracil nucleotides (Fig. 1a).[7] In this pathway, DHODH, a ubiquitously expressed mitochondrial inner membrane protein, governs the rate-limiting step by catalyzing the conversion of dihydroorotate to orotate through an oxidation reaction.[6,8,9] It is widely established that nucleotide synthesis is frequently enhanced in cancer cells, to meet the increased demand for rapid cell proliferation.[10] how DHODH is modulated in OSCC, and the role of DHODH in the regulation of OSCC cell proliferation remains elusive. Mechanistic study shows that the aberrant expression of DHODH in OSCC is regulated at transcriptional level by transcription factor SOX2
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