TY - JOUR
T1 - Food-Derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites
AU - Kurata, Masashi
AU - Fujiwara, Naoko
AU - Fujita, Ken ichi
AU - Yamanaka, Yasutaka
AU - Seno, Shigeto
AU - Kobayashi, Hisato
AU - Miyamae, Yusaku
AU - Takahashi, Nobuyuki
AU - Shibuya, Yasuyuki
AU - Masuda, Seiji
N1 - Funding Information:
We thank Dr. Robin Reed for the gifts of antibodies against SF3B1 and U2AF65 and Mr. Yuzo Watanabe for help with the LC-MS/MS analysis. We also thank Dr. Michael Antoniou for providing the β-globin reporter and Mr. Soichi Nishimura for technical assistance. Moreover, we are grateful to Kyowa Hakko Kirin Co., Ltd., for providing GEX1A. This work was supported in part by “Grants-in-Aid” from JSPS KAKENHI (Grant Numbers 26292053 , 17K19232 , 19K22280 , and 19H02884 to S.M, 19K15807 to K.F, and 15K11299 to Y.S.). This work was also supported in part by “Grants-in-Aid” from The Tojuro Iijima Foundation for Food Science and Technology , The Public Foundation of Elizabeth Arnold-Fuji , The Kieikai Research Foundation , Fuji Foundation for Protein Research , The Skylark Food Science Institute , and The Kyoto University Foundation to S.M. Moreover, this work was supported in part by “Grants-in-Aid” from The Sasakawa Scientific Research Grant from The Japan Science Society to M.K. This work was also supported by the Cooperative Research Grant of the Genome Research for BioResource , NODAI Genome Research Center , Tokyo University of Agriculture . The authors would like to thank Enago ( www.enago.com ) and Ms. Nozomi Ojima for the English language review.
Funding Information:
We thank Dr. Robin Reed for the gifts of antibodies against SF3B1 and U2AF65 and Mr. Yuzo Watanabe for help with the LC-MS/MS analysis. We also thank Dr. Michael Antoniou for providing the ?-globin reporter and Mr. Soichi Nishimura for technical assistance. Moreover, we are grateful to Kyowa Hakko Kirin Co. Ltd. for providing GEX1A. This work was supported in part by ?Grants-in-Aid? from JSPS KAKENHI (Grant Numbers 26292053, 17K19232, 19K22280, and 19H02884 to S.M, 19K15807 to K.F, and 15K11299 to Y.S.). This work was also supported in part by ?Grants-in-Aid? from The Tojuro Iijima Foundation for Food Science and Technology, The Public Foundation of Elizabeth Arnold-Fuji, The Kieikai Research Foundation, Fuji Foundation for Protein Research, The Skylark Food Science Institute, and The Kyoto University Foundation to S.M. Moreover, this work was supported in part by ?Grants-in-Aid? from The Sasakawa Scientific Research Grant from The Japan Science Society to M.K. This work was also supported by the Cooperative Research Grant of the Genome Research for BioResource, NODAI Genome Research Center, Tokyo University of Agriculture. The authors would like to thank Enago (www.enago.com) and Ms. Nozomi Ojima for the English language review. M.K. Y.S. and S.M. conceived the study; M.K. and Y.Y. conducted biological experiments; H.K. and N.T. performed RNA-seq; M.K. N.F. K.F. and S.S. performed bioinformatic analysis; Y.M. performed docking studies; M.K. and S.S. performed statistical analysis; and M.K. N.F. K.F. and S.M. analyzed the results and wrote the paper. All authors reviewed the final manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2019 The Authors
PY - 2019/12/20
Y1 - 2019/12/20
N2 - Cancer cells often exhibit extreme sensitivity to splicing inhibitors. We identified food-derived flavonoids, apigenin and luteolin, as compounds that modulate mRNA splicing at the genome-wide level, followed by proliferation inhibition. They bind to mRNA splicing-related proteins to induce a widespread change of splicing patterns in treated cells. Their inhibitory activity on splicing is relatively moderate, and introns with weak splice sites tend to be sensitive to them. Such introns remain unspliced, and the resulting intron-containing mRNAs are retained in the nucleus, resulting in the nuclear accumulation of poly(A)+ RNAs in these flavonoid-treated cells. Tumorigenic cells are more susceptible to these flavonoids than nontumorigenic cells, both for the nuclear poly(A)+ RNA-accumulating phenotype and cell viability. This study illustrates the possible mechanism of these flavonoids to suppress tumor progression in vivo that were demonstrated by previous studies and provides the potential of daily intake of moderate splicing inhibitors to prevent cancer development. Molecular Biology
AB - Cancer cells often exhibit extreme sensitivity to splicing inhibitors. We identified food-derived flavonoids, apigenin and luteolin, as compounds that modulate mRNA splicing at the genome-wide level, followed by proliferation inhibition. They bind to mRNA splicing-related proteins to induce a widespread change of splicing patterns in treated cells. Their inhibitory activity on splicing is relatively moderate, and introns with weak splice sites tend to be sensitive to them. Such introns remain unspliced, and the resulting intron-containing mRNAs are retained in the nucleus, resulting in the nuclear accumulation of poly(A)+ RNAs in these flavonoid-treated cells. Tumorigenic cells are more susceptible to these flavonoids than nontumorigenic cells, both for the nuclear poly(A)+ RNA-accumulating phenotype and cell viability. This study illustrates the possible mechanism of these flavonoids to suppress tumor progression in vivo that were demonstrated by previous studies and provides the potential of daily intake of moderate splicing inhibitors to prevent cancer development. Molecular Biology
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U2 - 10.1016/j.isci.2019.11.033
DO - 10.1016/j.isci.2019.11.033
M3 - Article
AN - SCOPUS:85075786863
VL - 22
SP - 336
EP - 352
JO - iScience
JF - iScience
SN - 2589-0042
ER -