Targeting Epigenetic and Posttranscriptional Gene Regulation by PSF Impairs Hormone Therapy-Refractory Cancer Growth.

Abstract

RNA-binding protein PSF functions as an epigenetic modifier by interacting with long noncoding RNAs and the corepressor complex. PSF also promotes RNA splicing events to enhance oncogenic signals. In this study, we conducted an in vitro chemical array screen and identified multiple small molecules that interact with PSF. Several molecules inhibited RNA binding by PSF and decreased prostate cancer cell viability. Among these molecules and its derivatives was a promising molecule, No. 10-3 [7,8-dihydroxy-4-(4-methoxyphenyl)chromen-2-one], that was the most effective at blocking PSF RNA-binding ability and suppressing treatment-resistant prostate and breast cancer cell proliferation. Exposure to No. 10-3 inhibited PSF target gene expression at the mRNA level. Treatment with No. 10-3 reversed epigenetically repressed PSF downstream targets, such as cell-cycle inhibitors, at the transcriptional level. Chromatin immunoprecipitation sequencing in prostate cancer cells revealed that No. 10-3 enhances histone acetylation to induce expression of apoptosis as well as cell-cycle inhibitors. Furthermore, No. 10-3 exhibited antitumor efficacy in a hormone therapy-resistant prostate cancer xenograft mouse model, suppressing treatment-resistant tumor growth. Taken together, this study highlights the feasibility of targeting PSF-mediated epigenetic and RNA-splicing activities for the treatment of aggressive cancers. SIGNIFICANCE: This study identifies small molecules that target PSF-RNA interactions and suppress hormone therapy-refractory cancer growth, suggesting the potential of targeting PSF-mediated gene regulation for cancer treatment.

• Authors: Ken-Ichi Takayama, Teruki Honma, Takashi Suzuki, Yasumitsu Kondoh, Hiroyuki Osada, Yutaka Suzuki, Minoru Yoshida, Satoshi Inoue
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 13 Pg. 3495-3508 (07 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33975881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• PTB-Associated Splicing Factor
• RNA, Long Noncoding
• Small Molecule Libraries

Topics

• Animals
• Apoptosis
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Epigenesis, Genetic
• Female
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• PTB-Associated Splicing Factor (genetics, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• RNA Processing, Post-Transcriptional
• RNA, Long Noncoding (genetics, metabolism)
• Small Molecule Libraries (pharmacology)
• Transcription, Genetic
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays