Format

Send to

Choose Destination
Sci Rep. 2017 Aug 4;7(1):7290. doi: 10.1038/s41598-017-07472-6.

4β-Hydroxywithanolide E Modulates Alternative Splicing of Apoptotic Genes in Human Hepatocellular Carcinoma Huh-7 Cells.

Lee CC1, Chang WH2, Chang YS1,3,4, Liu TY4, Chen YC4, Wu YC5,6,7, Chang JG8,9,10,11.

Author information

1
Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan.
2
Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
3
Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan.
4
Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan.
5
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan. yachwu@mail.cmu.edu.tw.
6
Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan. yachwu@mail.cmu.edu.tw.
7
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan. yachwu@mail.cmu.edu.tw.
8
Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan. d6781@mail.cmuh.org.tw.
9
Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan. d6781@mail.cmuh.org.tw.
10
Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan. d6781@mail.cmuh.org.tw.
11
Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan. d6781@mail.cmuh.org.tw.

Abstract

Alternative splicing is a mechanism for increasing protein diversity from a limited number of genes. Studies have demonstrated that aberrant regulation in the alternative splicing of apoptotic gene transcripts may contribute to the development of cancer. In this study, we isolated 4β-Hydroxywithanolide E (4bHWE) from the traditional herb Physalis peruviana and investigated its biological effect in cancer cells. The results demonstrated that 4bHWE modulates the alternative splicing of various apoptotic genes, including HIPK3, SMAC/DIABLO, and SURVIVIN. We also discovered that the levels of SRSF1 phospho-isoform were decreased and the levels of H3K36me3 were increased in 4bHWE treatment. Knockdown experiments revealed that the splicing site selection of SMAC/DIABLO could be mediated by changes in the level of H3K36me3 in 4bHWE-treated cells. Furthermore, we extended our study to apoptosis-associated molecules, and detected increased levels of poly ADP-ribose polymerase cleavage and the active form of CASPASE-3 in 4bHWE-induced apoptosis. In vivo experiments indicated that the treatment of tumor-bearing mice with 4bHWE resulted in a marked decrease in tumor size. This study is the first to demonstrate that 4bHWE affects alternative splicing by modulating splicing factors and histone modifications, and provides a novel view of the antitumor mechanism of 4bHWE.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center