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

Autor: Shen P; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Ye K; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Xiang H; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Zhang Z; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., He Q; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Zhang X; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Cai MC; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Chen J; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Sun Y; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Lin L; Ovarian Cancer Program, Department of Gynecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China., Qi C; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Zhang M; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Cheung LWT; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Shi T; Ovarian Cancer Program, Department of Gynecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China., Yin X; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li Y; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Di W; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zang R; Ovarian Cancer Program, Department of Gynecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China., Tan L; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Zhuang G; State 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.; Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Nov 24; Vol. 9 (47), pp. eadj0123. Date of Electronic Publication: 2023 Nov 22.
DOI: 10.1126/sciadv.adj0123
Abstrakt: 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.
Databáze: MEDLINE