TY - JOUR
T1 - Nucleoporin TPR (translocated promoter region, nuclear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma
AU - Dewi, Firli Rahmah Primula
AU - Jiapaer, Shabierjiang
AU - Kobayashi, Akiko
AU - Hazawa, Masaharu
AU - Ikliptikawati, Dini Kurnia
AU - Hartono,
AU - Sabit, Hemragul
AU - Nakada, Mitsutoshi
AU - Wong, Richard W.
N1 - Funding Information:
We are grateful for the support provided by Günter Blobel, who inspired the TPR work presented here. This work was supported by a MEXT/JSPS KAKENHI Grant Number B-26293322 (to N.M.); 17H05874, 17K08655 (to R.W.) from MEXT Japan, and by grants from the Kobayashi International Scholarship Foundation (to N.M. and R.W), and the Shimadzu Science Foundation (to R. W.).
Publisher Copyright:
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - 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. Abbreviations: ATG: autophagy related; BECN1: beclin 1; BSA: bovine serum albumin; CQ: chloroquine; DMSO: dimethyl sulfoxide; GEO: gene expression omnibus; GFP: green fluorescence protein; HSF1: heat shock transcription factor 1; HSPA/HSP70: heat shock protein family A (Hsp70); LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTORC1: mechanistic target of rapamycin kinase complex 1; NPC: nuclear pore complex; NUP: nucleoporin; PBS: phosphate-buffered saline; q-PCR: quantitative real time PCR; SDS: sodium dodecyl sulfate; SQSTM1: sequestosome 1; STED: stimulated emission depletion microscopy; STX17: syntaxin 17; TCGA: the cancer genome atlas; TPR: translocated promoter region, nuclear basket protein; ULK1: unc-51 like autophagy activating kinase 1.
AB - 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. Abbreviations: ATG: autophagy related; BECN1: beclin 1; BSA: bovine serum albumin; CQ: chloroquine; DMSO: dimethyl sulfoxide; GEO: gene expression omnibus; GFP: green fluorescence protein; HSF1: heat shock transcription factor 1; HSPA/HSP70: heat shock protein family A (Hsp70); LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTORC1: mechanistic target of rapamycin kinase complex 1; NPC: nuclear pore complex; NUP: nucleoporin; PBS: phosphate-buffered saline; q-PCR: quantitative real time PCR; SDS: sodium dodecyl sulfate; SQSTM1: sequestosome 1; STED: stimulated emission depletion microscopy; STX17: syntaxin 17; TCGA: the cancer genome atlas; TPR: translocated promoter region, nuclear basket protein; ULK1: unc-51 like autophagy activating kinase 1.
KW - Autophagy
KW - HSF1
KW - MTORC1
KW - TPR
KW - ependymoma
UR - http://www.scopus.com/inward/record.url?scp=85082414066&partnerID=8YFLogxK
U2 - 10.1080/15548627.2020.1741318
DO - 10.1080/15548627.2020.1741318
M3 - Article
C2 - 32207633
AN - SCOPUS:85082414066
SN - 1554-8627
VL - 17
SP - 1001
EP - 1012
JO - Autophagy
JF - Autophagy
IS - 4
ER -
