Abstract
The existence of the blood–tumor barrier (BTB) severely hinders the transport of anti-tumor drugs to brain tumor tissues. Selectively opening BTB is of great significance to improve the chemotherapy effect of glioma. Pseudogenes have been recognized as important regulators in various biologic processes. In this study, we identified that ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs). Knockdown of RPL32P3 decreased the expression of tight junction-related proteins (TJPs) and increased BTB permeability. Subsequent analysis of the underlying mechanism indicated that RPL32P3 recruited lysine methyltransferase 2 A (KMT2A) to the Y-box binding protein 2 (YBX2) promoter region and mediated H3K4me3 to promote YBX2 transcription. Highly expressed YBX2 bound and stabilized hepatocyte nuclear factor 4 gamma (HNF4G) mRNA. Highly expressed HNF4G directly bound to the promoters of TJPs ZO-1, occludin and claudin-5 to promote their transcriptional activities and regulated BTB permeability. The simultaneous knockdown of RPL32P3, YBX2, and HNF4G combined with doxorubicin (DOX) increased the apoptosis of glioma cells. In conclusion, the current study indicated that RPL32P3 knockdown increased BTB permeability through the YBX2/HNF4G pathway. These findings may provide new targets for the comprehensive treatment of glioma.
Highlights
Glioma is one of the most common primary malignant tumors in the central nervous system [1, 2]
This study found for the first time that Ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs)
Pseudogene RPSAP52 positively regulates the transcription of HMGA2 in the nucleus and acts as a translational co-regulator with LIN28B and HMGA2 mRNAs in the cytoplasm to regulate the function of IGF2BP2 protein; RPSAP52 regulates the HMGA2/IGF2BP2/LIN28B axis through a double mechanism to show the oncogene characteristics in breast cancer, rhabdomyosarcoma, Ewing’s sarcoma and other human tumors [24]
Summary
Glioma is one of the most common primary malignant tumors in the central nervous system [1, 2]. Due to the existence of blood–tumor barrier (BTB), the transport of drugs to tumor tissue is seriously limited, which attenuates the chemotherapeutic effect [4]. BTB is composed of brain tumor cells, highly specific brain microvascular endothelial cells (ECs) called glioma-exposed endothelial cells (GECs), astrocytes and pericytes, and has some characteristics of blood-brain barrier (BBB). How to open BTB effectively and selectively is of great significance to improve the chemotherapeutic effect of glioma. According to the genome composition and the relationship with the coding gene, the transcribed pseudogenes are classified as a type of lncRNAs [5]. It would be of great significance to identify pseudogenes associated with tumors and clarify their mechanism of action. Little is known about their expression and function in GECs
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