Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer
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Yujiro Nishizawa1,2,*, Masamitsu Konno2,3,*, Ayumu Asai2,3, Jun Koseki3, Koichi Kawamoto1,2, Norikatsu Miyoshi1, Hidekazu Takahashi1, Naohiro Nishida1, Naotsugu Haraguchi1, Daisuke Sakai2, Toshihiro Kudo2, Taishi Hata1, Chu Matsuda1, Tsunekazu Mizushima1,4, Taroh Satoh2, Yuichiro Doki1, Masaki Mori1 and Hideshi Ishii2,3
1Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
2Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
3Department of Disease Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
4Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
*These authors contributed equally to this work
Hideshi Ishii, email: [email protected]
Masaki Mori, email: [email protected]
Keywords: YTHDF1; colorectal cancer; c-MYC; proliferation; chemosensitivity
Received: August 31, 2017 Accepted: October 28, 2017 Published: December 21, 2017
Recent studies that have emerged on the diversity of RNA modification in tumors suggest their eligibility as bona fide targets in diagnosis and drug discovery. N6-methyladenosine (m6A) was first reported and is most common in epitranscriptome modification of various RNAs. The YT521-B homology (YTH) domain family are representative m6A-binding proteins, but how the YTH domain family is involved in cancer remains to be clearly understood. Given that clinical sequence data in colorectal cancer indicate that overexpression of YTHDF1 is outstanding among other family members, we studied the role of Ythdf1 and the transcriptional control of YTHDF1. Immunostaining of Ythdf1 showed that its expression was associated with various malignant tumor behaviors, such as depth, lymph node metastasis, and poorer cancer stages. The study of patient survival indicated that patients with high Ythdf1 expression had significantly poorer overall survival. The results indicated that Ythdf1 expression is an independent prognostic factor of patients. The in vitro study showed that the knockdown of YTHDF1 resulted in the suppression of cancer proliferation and sensitization to the exposure of anticancer drugs such as fluorouracil and oxaliplatin. Importantly, the study upstream of the YTHDF1 gene indicated that an oncogenic transcription factor c-Myc was associated with YTHDF1 in both expression and chromatin immunoprecipitation data. Moreover, the knockdown experiments of c-Myc showed the inhibition of YTHDF1, supporting a notion of c-Myc-driven YTHDF1 axis significance. These data suggest that m6A reader Ythdf1 plays a significant role in colorectal cancer progression.
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