Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma.
BACKGROUND
ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to investigate the significance of ATAD3A in glioblastoma multiforme (GBM).


METHODS
Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair-associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting.


RESULTS
Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment.


CONCLUSIONS
Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.
Corresponding Author: Kuan-Chih Chow, PhD, Graduate Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan. kcchow@dragon.nchu.edu.tw.
Weir-Chiang
WC
You
Shiow-Her
SH
Chiou
Chih-Yang
CY
Huang
Shu-Fen
SF
Chiang
Cheng-Lin
CL
Yang
Janaki N
JN
Sudhakar
Tze-Yi
TY
Lin
I-Ping
IP
Chiang
Chiung-Chyi
CC
Shen
Wen-Yu
WY
Cheng
Jin-Chin
JC
Lin
Shwn-Huey
SH
Shieh
Kuan-Chih
KC
Chow
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D002454:Cell Differentiation; D049109:Cell Proliferation; D059248:Chemoradiotherapy; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
C549686:ATAD3A protein, human; D018906:Antineoplastic Agents, Alkylating; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; D000077204:Temozolomide
ATAD3A; DNA repair; autophagy; glioblastoma multiforme; radiation