Nucleoporin TPR (translocated promoter region, nuclear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma

Abstract

Children with ependymoma have high mortality rates because ependymoma is resistant to conventional therapy. Genomic and transcriptomic studies have identified potential targets as significantly altered genes in ependymoma patients. Although several candidate oncogenes in ependymoma were recently reported, the detailed mechanisms for the roles of these candidate oncogenes in ependymoma progression remain unclear. Here, we report an oncogenic role of the nucleoporin TPR (translocated promoter region, nuclear basket protein) in regulating HSF1 (heat shock transcription factor 1) mRNA trafficking, maintaining MTORC1 activity to phosphorylate ULK1, and preventing macroautophagy/ autophagy induction in ependymoma. High expression of TPR were associated with increased HSF1 and HSPA/HSP70 expression in ependymoma patients. In an ependymoma mouse xenograft model, MTOR inhibition by rapamycin therapeutically suppressed TPR expression and reduced tumor size in vivo. Together, these results suggest that TPR may act as a biomarker for ependymoma, and pharmacological interventions targeting TPR-HSF1-MTOR may have therapeutic potential for ependymoma treatment.

Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex

“…Cells were then rinsed and incubated with secondary antibodies in 4% BSA/PBS (1:500 dilution) for 2 h at room temperature. After washing with PBS, coverslips were mounted on slides using ProLong Diamond Antifade reagent with DAPI (Invitrogen, P36966), and observed on a confocal laser-scanning microscope with 60X PlanApo/1.45NA DIC objective (Olympus, FV10i-LIV), as previously described [ 27 ].…”

“…Nuclear/cytoplasmic fractionation analysis was performed using nuclear and cytoplasmic extraction reagents according to the manufacturer's protocol (Thermo Scientific, 78840), as previously described [ 25 , 27 ]. Cytoplasmic and nuclear extracts were then subjected to immunoblotting analysis.…”

“…The following day, beads were washed three times with lysis buffer. Whole-cell lysates and immunoprecipitates were analyzed by immunoblotting, as previously described [ 27 ].…”

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

“…The role of autophagy in ependymoma has not been specifically investigated so far. However, a study concerning the role of nucleoporin TPR upregulation within this tumour attracted the interest of researchers in regard to its connection with autophagy, given the existing correlation between TPR depletion and autophagy induction in HeLa cells [ 126 ]. By analysing mRNA expression levels of autophagy-related proteins, Dewi’s research team found that ATG3 , ATG5 , ATG12, and Beclin 1 expression is significantly downregulated in ependymoma patients [ 127 ].…”

The Long Non-coding RNA LINC01705 Regulates the Development of Breast Cancer by Sponging miR-186-5p to Mediate TPR Expression as a Competitive Endogenous RNA

“…TPR has been since implicated in a variety of nuclear functions, including mitosis, regulation of transcription, chromatin organization, and nuclear transport (Snow and Paschal, 2014). A study showed that high expression of TPR is associated with ependymoma and TPR may act as a biomarker for ependymoma (Dewi et al, 2020). TPR is also related to some other cancer progression, including colorectal cancer (Dewi et al, 2018), lung adenocarcinoma (Choi et al, 2014) and so on.…”