Downregulation of COUP‑TFII inhibits glioblastoma growth via targeting MPC1

Abstract

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is a steroid receptor that is broadly expressed in many tissues throughout embryonic development. Previous studies indicated that COUP-TFII is dysregulated in multiple types of cancer and serves crucial roles in cancer development. The mitochondrial pyruvate carrier 1 (MPC1) is involved in transporting pyruvate for entry into the citric acid cycle, an important event in cancer progression. However, the roles of COUP-TFII and MPC1 in glioma remain unknown. In the present study, it was demonstrated that MPC1 is downregulated in glioblastoma. Furthermore, the inhibition of COUP-TFII was able to increase MPC1 expression and inhibit the growth of glioblastoma cells in vitro and in vivo. The findings from the present study demonstrated that downregulation of COUP-TFII inhibits glioblastoma growth via targeting MPC1. Therefore, COUP-TFII is a potential therapeutic target for glioma.

Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

“…Similarly, a TCGA analysis of isocitrate dehydrogenase (IDH)-mutant gliomas associates increased MPC1 expression with overall survival [ 34 ]. Increased MPC1 expression via COUP-TFII inhibition slows growth of human glioblastoma cell lines and decreases tumor volume in xenograft studies with immune-deficient mice [ 35 ]. Although these studies suggest that MPC disruption in glioblastoma exacerbates tumor aggressiveness, studies of MPC inhibition or knockout in glioblastoma mouse models would strengthen these findings.…”

“…There is also clinical evidence that a ketogenic diet may increase progression-free and overall survival for glioblastoma patients by reducing glucose availability for tumors [ 38 ]. These clinical studies [ 36 , 37 , 38 ] suggest that glioblastoma tumors exhibit increased pyruvate metabolism in vivo, which is difficult to resolve with the low levels of MPC expression observed in TCGA, cell culture, and xenograft studies [ 33 , 34 , 35 ]. Overall, more in vivo studies testing the direct contribution of the MPC to glioblastoma progression are needed to understand the role of pyruvate oxidation in brain cancer.…”

“…Several transcription factors have been shown to regulate MPC1/2 expression in various tissues and diseases. In cancer, upregulation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) transcript expression downregulates MPC1 expression to drive cell growth and metastasis in prostate cancer and glioblastoma [ 32 , 35 ]. In androgen-receptor-positive prostate cancers, androgen receptor binding to the intron of the MPC2 locus directly controls transcription of MPC2 [ 49 ].…”

Oligonucleotide Therapeutics as a New Class of Drugs for Malignant Brain Tumors: Targeting mRNAs, Regulatory RNAs, Mutations, Combinations, and Beyond

“…GSCs are reported to have activated POU3F2, SALL2, SOX2, and OLIG2, all four simultaneously, and in combination, and the inhibition of each one leads to the reversible loss of tumorigenicity [ 138 ]. In addition to these presumed driver transcription factors, other signaling pathways are also activated, such as Wnt/β-catenin, Notch, PI3K, NF-κB, SHH/GLI, COUP-TFII, and JAK/STAT/stathmin [ 139 – 144 ]. Members of the STAT family of transcription factors are of particular interest as key regulators of cell growth, angiogenesis, motility, and immune response [ 145 ].…”

<p>lncRNA small nucleolar RNA host gene 20 predicts poor prognosis in glioma and promotes cell proliferation by silencing P21</p>

“…As the most common central nervous system malignant tumor, glioma has the characteristics of poor prognosis, aggressiveness, rapid progression and frequent recurrence 1. In particular, the median survival time of patients with glioblastoma was shorter than 1 year 2. Obviously, dismal was remained in the prognosis for glioma patients although there are a variety of treatment options, such as chemotherapy, radiotherapy and surgery 3.…”