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.
Sci Adv. 2023 Nov 24;9(47):eadj0123. doi: 10.1126/sciadv.adj0123. Epub 2023 Nov 22.
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.
转录失调是卵巢癌中反复出现的致病特征和新兴治疗弱点。在这里，我们证明卵巢癌表现出对转录终止调节机制的独特依赖性，特别是切割和多聚腺苷酸化特异性因子 (CPSF) 复合物。多个 CPSF 亚基的遗传缺失严重阻碍了肿瘤细胞的活力，我们提供的证据表明，它们不可或缺的作用集中在内切核酸酶 CPSF3 上。在机制上，CPSF 扰动导致 3'-非翻译区延长、内含子多聚腺苷酸化减少和广泛的转录通读，从而抑制致癌途径。此外，我们报告了基于苯并恶硼烷支架开发的特异性 CPSF3 抑制剂，这些抑制剂具有很强的抗肿瘤活性。值得注意的是，CPSF3 阻断通过下调 DNA 损伤修复基因有效加剧基因组不稳定性，从而与聚（腺苷酸 5'-二磷酸-核糖）聚合酶抑制协同作用。这些发现确立了 CPSF3 依赖性转录终止作为卵巢癌可利用的驱动机制，并为靶向转录成瘾性人类恶性肿瘤提供了一类有前途的含硼化合物。
