Abstract
Thyroid cancer has become the most frequent endocrine-related malignancy. Currently, a mounting body of evidences support the clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers. However, the functions and molecular mechanisms of PARP inhibitors in thyroid cancers (TCs) are not fully understood. Here, on the one hand, we revealed that niraparib promotes the accumulation of DNA damage in TCs. On the other hand, we indicated that niraparib inhibits the transcription of DIMT1 through promoting Pol II pausing in a PAR-dependent manner, subsequently leading to a global translation inhibition in TCs. Meanwhile, we found that niraparib activates the NF-κB signaling pathway by inhibiting the PARylation of p65, which decreases its ubiquitination and degradation level through E3 ubiquitin ligase RNF146. Moreover, bortezomib (a small molecule inhibitor of the NF-κB signaling pathway) could significantly enhance the anti-tumor effect of niraparib on TCs in vitro and in vivo. Our findings provide mechanistic supports for the efficacy of PARP inhibitors in cancer cells lacking BRCA-mutant.