TY - JOUR
T1 - N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma
AU - Tatekawa, Shotaro
AU - Tamari, Keisuke
AU - Chijimatsu, Ryota
AU - Konno, Masamitsu
AU - Motooka, Daisuke
AU - Mitsufuji, Suguru
AU - Akita, Hirofumi
AU - Kobayashi, Shogo
AU - Murakumo, Yoshiki
AU - Doki, Yuichiro
AU - Eguchi, Hidetoshi
AU - Ishii, Hideshi
AU - Ogawa, Kazuhiko
N1 - Funding Information:
We thank Ms. Miyuki Osaki and Ms. Yasuko Arao, for technical assistance. This study was supported by Hiroshi Yamasaki and Center for Medical Research and Education, Graduate School of Medicine, Osaka University. This work received financial support from grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (Grant Nos. 21K19526, 20H00541, 18KK0251, and 18K15631). Partial support was received from Princess Takamatsu Cancer Research Fund and Mitsubishi Foundation, to H.I. and the Takeda Science Foundation, to S.T.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - In pancreatic cancer, methyltransferase-like 3 (METTL3), a N(6)-methyladenosine (m6A) methyltransferase, has a favorable effect on tumors and is a risk factor for patients’ prognosis. However, the details of what genes are regulated by METTL3 remain unknown. Several RNAs are methylated, and what genes are favored in pancreatic cancer remains unclear. By epitranscriptomic analysis, we report that polo-like kinase 1 (PLK1) is an important hub gene defining patient prognosis in pancreatic cancer and that RNA methylation is involved in regulating its cell cycle-specific expression. We found that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to m6A of PLK1 3′ untranslated region and is involved in upregulating PLK1 expression and that demethylation of this site activates the ataxia telangiectasia and Rad3-related protein pathway by replicating stress and increasing mitotic catastrophe, resulting in increased radiosensitivity. This suggests that PLK1 methylation is essential for cell cycle maintenance in pancreatic cancer and is a new therapeutic target.
AB - In pancreatic cancer, methyltransferase-like 3 (METTL3), a N(6)-methyladenosine (m6A) methyltransferase, has a favorable effect on tumors and is a risk factor for patients’ prognosis. However, the details of what genes are regulated by METTL3 remain unknown. Several RNAs are methylated, and what genes are favored in pancreatic cancer remains unclear. By epitranscriptomic analysis, we report that polo-like kinase 1 (PLK1) is an important hub gene defining patient prognosis in pancreatic cancer and that RNA methylation is involved in regulating its cell cycle-specific expression. We found that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to m6A of PLK1 3′ untranslated region and is involved in upregulating PLK1 expression and that demethylation of this site activates the ataxia telangiectasia and Rad3-related protein pathway by replicating stress and increasing mitotic catastrophe, resulting in increased radiosensitivity. This suggests that PLK1 methylation is essential for cell cycle maintenance in pancreatic cancer and is a new therapeutic target.
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U2 - 10.1038/s41598-022-15196-5
DO - 10.1038/s41598-022-15196-5
M3 - Article
C2 - 35773310
AN - SCOPUS:85133292802
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11074
ER -
