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Novel role of CAP1 in regulation RNA polymerase II-mediated transcription elongation depends on its actin-depolymerization activity in nucleoplasm

Oncogene volume 40, pages 3492–3509 (2021)Cite this article

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Abstract

Lung cancer is one of the most intractable diseases with high incidence and mortality worldwide. Adenylate cyclase-associated protein 1 (CAP1), a well-known actin depolymerization factor, is recently reported to be an oncogene accelerating cancer cell proliferation. However, the physiological significance of CAP1 in lung cancer is incompletely understood and the novel functions of CAP1 in transcriptional regulation remain unknown. Here we found that CAP1 was highly expressed in lung cancer tissues and cells, which was also negatively associated with prognosis in lung cancer patients. Moreover, CAP1 promoted A549 cells proliferation by promoting protein synthesis to accelerate cell cycle progression. Mechanistically, we revealed that CAP1 facilitated cyclin-dependent kinase 9 (CDK9)-mediated RNA polymerases (Pol) II-Ser2 phosphorylation and subsequent transcription elongation, and CAP1 performed its function in this progress depending on its actin-depolymerization activity in nucleoplasm. Furthermore, our in vivo findings confirmed that CAP1-promoted A549 xenograft tumor growth was associated with CDK9-mediated Pol II-Ser2 phosphorylation. Our study elucidates a novel role of CAP1 in modulating transcription by promoting polymerase II phosphorylation and suggests that CAP1 is a newly identified biomarker for lung cancer treatment and prognosis prediction.

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Fig. 1: High CAP1 expression is a prognostic indicator of poor survival in lung cancer patients.
Fig. 2: CAP1 knockdown attenuates A549 cell growth and proliferation.
Fig. 3: Overexpression of CAP1 promotes A549 cell growth and proliferation.
Fig. 4: CAP1 accelerates A549 cell cycle progression.
Fig. 5: CAP1 is required for protein synthesis in A549 cells.
Fig. 6: CAP1 is necessary for RNA polymerase II (Pol II)-mediated transcription by phosphorylating Pol II at Ser 2 in the nucleoplasm.
Fig. 7: CDK9/Pol II-mediated transcriptional elongation depends on the actin-depolymerization activity of CAP1 in the nucleoplasm.
Fig. 8: CAP1 promotes tumor growth by enhancing CDK9-dependent Pol II-Ser2 phosphorylation in vivo.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant No. 81874357) and the Youth Talent Project of Army Medical University (Grant No. 2019R050).

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  1. These authors contributed equally: Qian Zhang, Qin Tang

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  1. Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China

    Qian Zhang, Qin Tang, Wuyi Liu, Changpeng Hu, Xiaoyu Liu, Yali Liu, Min Zhou, Wenjing Lai, Fangfang Sheng, Haibo Yang, Jingbin Huang & Guobing Li

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Contributions

QZ, QT, JH, and GL designed experiments; QZ, QT, WL, CH, FL, MZ, and YL performed all experiments; QZ, QT, WL, FS, XL, and HY analyzed the data; QZ, JH, and GL wrote the paper.

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Correspondence to Jingbin Huang or Guobing Li.

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Zhang, Q., Tang, Q., Liu, W. et al. Novel role of CAP1 in regulation RNA polymerase II-mediated transcription elongation depends on its actin-depolymerization activity in nucleoplasm. Oncogene 40, 3492–3509 (2021). https://doi.org/10.1038/s41388-021-01789-3

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