Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer.

Abstract

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3'-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.

• Authors: Peiye Shen, Kaiyan Ye, Huaijiang Xiang, Zhenfeng Zhang, Qinyang He, Xiao Zhang, Mei-Chun Cai, Junfei Chen, Yunheng Sun, Lifeng Lin, Chunting Qi, Meiying Zhang, Lydia W T Cheung, Tingyan Shi, Xia Yin, Ying Li, Wen Di, Rongyu Zang, Li Tan, Guanglei Zhuang
• Journal: Science advances (Sci Adv) Vol. 9 Issue 47 Pg. eadj0123 (11 24 2023) ISSN: 2375-2548 [Electronic] United States
• PMID: 37992178 (Publication Type: Journal Article)

Chemical References

• Cleavage And Polyadenylation Specificity Factor
• CPSF3 protein, human

Topics

• Female
• Humans
• Cleavage And Polyadenylation Specificity Factor (genetics, metabolism)
• Neoplasm Recurrence, Local
• Ovarian Neoplasms (drug therapy, genetics)