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Int J Biol Sci 2023; 19(12):3970-3986. doi:10.7150/ijbs.81895 This issue Cite

Research Paper

PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause

Xiukun Hou1#, Mengran Tian2,3,4#, Junya Ning1,2,3,4#, Zhongyu Wang1, Fengli Guo1, Wei Zhang2,3,4, Linfei Hu1, Songfeng Wei1, Chuanxiang Hu1, Xinwei Yun1, Jingzhu Zhao1, Qiman Dong5, Xianhui Ruan1, Dapeng Li1✉, Ming Gao1,2,3✉, Xiangqian Zheng1✉

1. Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300040, China.
2. Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.
3. Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin,300121, China.
4. School of Medicine, Nankai University, Tianjin 300071, China.
5. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Dapeng Li, lidapeng0203com; Ming Gao, headandneck2008com; Xiangqian Zheng, xzheng05edu.cn.

Citation:
Hou X, Tian M, Ning J, Wang Z, Guo F, Zhang W, Hu L, Wei S, Hu C, Yun X, Zhao J, Dong Q, Ruan X, Li D, Gao M, Zheng X. PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause. Int J Biol Sci 2023; 19(12):3970-3986. doi:10.7150/ijbs.81895. https://www.ijbs.com/v19p3970.htm
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Abstract

Graphic 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.

Keywords: PARP inhibitor, BRCAness genes, Pol II pausing, NF-κB signaling pathway, combination treatment

Citation styles

APA
Hou, X., Tian, M., Ning, J., Wang, Z., Guo, F., Zhang, W., Hu, L., Wei, S., Hu, C., Yun, X., Zhao, J., Dong, Q., Ruan, X., Li, D., Gao, M., Zheng, X. (2023). PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause. International Journal of Biological Sciences, 19(12), 3970-3986. https://doi.org/10.7150/ijbs.81895.

ACS
Hou, X.; Tian, M.; Ning, J.; Wang, Z.; Guo, F.; Zhang, W.; Hu, L.; Wei, S.; Hu, C.; Yun, X.; Zhao, J.; Dong, Q.; Ruan, X.; Li, D.; Gao, M.; Zheng, X. PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause. Int. J. Biol. Sci. 2023, 19 (12), 3970-3986. DOI: 10.7150/ijbs.81895.

NLM
Hou X, Tian M, Ning J, Wang Z, Guo F, Zhang W, Hu L, Wei S, Hu C, Yun X, Zhao J, Dong Q, Ruan X, Li D, Gao M, Zheng X. PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause. Int J Biol Sci 2023; 19(12):3970-3986. doi:10.7150/ijbs.81895. https://www.ijbs.com/v19p3970.htm

CSE
Hou X, Tian M, Ning J, Wang Z, Guo F, Zhang W, Hu L, Wei S, Hu C, Yun X, Zhao J, Dong Q, Ruan X, Li D, Gao M, Zheng X. 2023. PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause. Int J Biol Sci. 19(12):3970-3986.

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