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Cellular and Molecular Biology

STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression

British Journal of Cancer volume 128, pages 766–782 (2023)Cite this article

Subjects

Abstract

Background

Deregulation of either RNA polymerase I (Pol I)-directed transcription or expression of signal transducer and activator of transcription 3 (STAT3) correlates closely with tumorigenesis. However, the connection between STAT3 and Pol I-directed transcription hasn’t been investigated.

Methods

The role of STAT3 in Pol I-directed transcription was determined using combined techniques. The regulation of tumor cell growth mediated by STAT3 and Pol I products was analyzed in vitro and in vivo. RNAseq, ChIP assays and rescue assays were used to uncover the mechanism of Pol I transcription mediated by STAT3.

Results

STAT3 expression positively correlates with Pol I product levels and cancer cell growth. The inhibition of STAT3 or Pol I products suppresses cell growth. Mechanistically, STAT3 activates Pol I-directed transcription by enhancing the recruitment of the Pol I transcription machinery to the rDNA promoter. STAT3 directly activates Rpa34 gene transcription by binding to the RPA34 promoter, which enhances the occupancies of the Pol II transcription machinery factors at this promoter. Cancer patients with RPA34 high expression lead to poor survival probability and short survival time.

Conclusion

STAT3 potentiates Pol I-dependent transcription and tumor cell growth by activating RPA34 in vitro and in vivo.

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Fig. 1: Alteration of STAT3 expression affected Pol I-directed transcription.
Fig. 2: The positive role of STAT3 in Pol I-directed transcription was confirmed by a dCas9 activation and repression system as well as a STAT3 inhibitor.
Fig. 3: STAT3 promotes cancer cell proliferation.
Fig. 4: STAT3 downregulation inhibited tumor cell growth in vivo.
Fig. 5: STAT3-IN-3 and CX-5461 showed an additive effect on the inhibition of tumor cell growth in vitro and in vivo.
Fig. 6: STAT3 expression positively correlates with RPA34 expression at both RNA and protein levels.
Fig. 7: The relationship between RPA34 expression levels and survival probability and survival time in cancers.
Fig. 8: STAT3 regulates the assembly of components of the Pol I transcription machinery at the rDNA promoter by affecting RPA34 expression.
Fig. 9: STAT3 modulates Pol I–directed transcription by controlling RPA34 transcription.
Fig. 10: A proposed model by which STAT3 modulates Pol I-directed transcription.

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Data availability

The RNA-seq data about SaOS2 cell FLNA silencing were deposited in the NCBI repository (SRA: SRP318361, https://www.ncbi.nlm.nih.gov/Traces/study/?acc=PRJNA726417). The RNA-seq data about HepG2 cell STAT3 silencing were deposited in the NCBI Gene Expression Omnibus (GSE201548). The RNA-seq data used for Pearson correlation analysis, Kaplan–Meier plotting and Violin plotting were obtained from the TCGA database (www.tcgaportal.org).

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Funding

This work was funded by the National Natural Science Foundation of China (31671357 to WD, 62172312 to SZhang).

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Authors and Affiliations

  1. School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China

    Cheng Zhang, Juan Wang, Xiaoye Song, Deen Yu, Xiaomei Yin, Shasha Zhao, Huan Deng, Shihua Zhang & Wensheng Deng

  2. School of Materials and Metallurgy, Wuhan University of Science and Technology, Wuhan, 430081, China

    Juan Wang

  3. Department of Life Sciences, Manchester Metropolitan University, Manchester, M15 6BH, UK

    Baoqiang Guo

  4. Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3GE, UK

    Yaoyu Pang

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  1. Cheng Zhang
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Contributions

CZ performed most work in Figs. 1–8 and in the supplementary file; JW validated data and mentored researchers; YS and DY performed cell culture and cell line screening; YP and BG performed gene cloning; HD prepared CRPSR dCas9 expression system, designed experiments and performed a part of supervision work; XY performed RPA34 shRNA cloning; SZhang and SZhao performed most of the supervision work, processed data, and edited the manuscript; WD acquired the fund of this work, designed experiments, processed data, and wrote the manuscript.

Corresponding authors

Correspondence to Shasha Zhao, Huan Deng, Shihua Zhang or Wensheng Deng.

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The authors declare no competing interests.

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Animal experiments were approved by the Animal and Medical Ethics Committee of School of Life Science and Health at Wuhan University of Science and Technology. The animal protocols abided by the Animal Welfare Guidelines (China).

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Zhang, C., Wang, J., Song, X. et al. STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression. Br J Cancer 128, 766–782 (2023). https://doi.org/10.1038/s41416-022-02098-6

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