Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.
Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ-induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM.
Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
Tomohiro
T
Yamaki
Yusuke
Y
Suenaga
Toshihiko
T
Iuchi
Jennifer
J
Alagu
Atsushi
A
Takatori
Makiko
M
Itami
Akinobu
A
Araki
Miki
M
Ohira
Masahiro
M
Inoue
Hajime
H
Kageyama
Sana
S
Yokoi
Naokatsu
N
Saeki
Akira
A
Nakagawara
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D000077204:Temozolomide; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D016271:Proto-Oncogene Proteins c-myc; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D000077204:Temozolomide