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Published on: August 2, 2024
Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer
Peiye Shen1,2, Kaiyan Ye1,2, Huaijiang Xiang3,4
1State Key Laboratory of Systems Medicine for Cancer, Department of Obstetrics and Gynecology, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Ovarian cancer depends on transcriptional termination factors like CPSF. Inhibiting CPSF3, a key endonuclease, halts cancer growth and enhances DNA damage, offering a new therapeutic strategy.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Transcriptional dysregulation is a hallmark of ovarian cancer.
- The cleavage and polyadenylation specificity factor (CPSF) complex plays a critical role in gene expression regulation.
Purpose of the Study:
- To investigate the role of the CPSF complex in ovarian cancer.
- To identify and develop novel therapeutic targets within the CPSF machinery.
Main Methods:
- Genetic abrogation of CPSF subunits in ovarian cancer cells.
- Analysis of 3'-untranslated regions, polyadenylation, and transcriptional readthrough.
- Development and testing of CPSF3 inhibitors based on the benzoxaborole scaffold.
- Assessment of genomic instability and synergy with PARP inhibitors.
Main Results:
- Ovarian cancer cells exhibit a dependency on CPSF complex function.
- CPSF3 was identified as a critical endonuclease within the complex.
- CPSF perturbation leads to altered RNA processing, suppressed oncogenic pathways, and reduced cell viability.
- CPSF3 inhibitors demonstrated potent antitumor activity and exacerbated genomic instability.
- CPSF3 inhibition synergized with poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors.
Conclusions:
- CPSF3-dependent transcriptional termination is a key driver in ovarian cancer.
- Targeting CPSF3 represents a promising therapeutic strategy for ovarian cancer.
- Benzoxaborole-based CPSF3 inhibitors offer a novel class of compounds for treating transcription-addicted malignancies.
