Cargando…

SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells

Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruv...

Descripción completa

Detalles Bibliográficos
Autores principales: Kuranaga, Yuki, Sugito, Nobuhiko, Shinohara, Haruka, Tsujino, Takuya, Taniguchi, Kohei, Komura, Kazumasa, Ito, Yuko, Soga, Tomoyoshi, Akao, Yukihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213643/
https://www.ncbi.nlm.nih.gov/pubmed/30279379
http://dx.doi.org/10.3390/ijms19103012
_version_ 1783367817144303616
author Kuranaga, Yuki
Sugito, Nobuhiko
Shinohara, Haruka
Tsujino, Takuya
Taniguchi, Kohei
Komura, Kazumasa
Ito, Yuko
Soga, Tomoyoshi
Akao, Yukihiro
author_facet Kuranaga, Yuki
Sugito, Nobuhiko
Shinohara, Haruka
Tsujino, Takuya
Taniguchi, Kohei
Komura, Kazumasa
Ito, Yuko
Soga, Tomoyoshi
Akao, Yukihiro
author_sort Kuranaga, Yuki
collection PubMed
description Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.
format Online
Article
Text
id pubmed-6213643
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62136432018-11-14 SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells Kuranaga, Yuki Sugito, Nobuhiko Shinohara, Haruka Tsujino, Takuya Taniguchi, Kohei Komura, Kazumasa Ito, Yuko Soga, Tomoyoshi Akao, Yukihiro Int J Mol Sci Article Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism. MDPI 2018-10-02 /pmc/articles/PMC6213643/ /pubmed/30279379 http://dx.doi.org/10.3390/ijms19103012 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kuranaga, Yuki
Sugito, Nobuhiko
Shinohara, Haruka
Tsujino, Takuya
Taniguchi, Kohei
Komura, Kazumasa
Ito, Yuko
Soga, Tomoyoshi
Akao, Yukihiro
SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title_full SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title_fullStr SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title_full_unstemmed SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title_short SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells
title_sort srsf3, a splicer of the pkm gene, regulates cell growth and maintenance of cancer-specific energy metabolism in colon cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213643/
https://www.ncbi.nlm.nih.gov/pubmed/30279379
http://dx.doi.org/10.3390/ijms19103012
work_keys_str_mv AT kuranagayuki srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT sugitonobuhiko srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT shinoharaharuka srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT tsujinotakuya srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT taniguchikohei srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT komurakazumasa srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT itoyuko srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT sogatomoyoshi srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells
AT akaoyukihiro srsf3asplicerofthepkmgeneregulatescellgrowthandmaintenanceofcancerspecificenergymetabolismincoloncancercells