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Int J Biol Sci 2023; 19(16):5319-5336. doi:10.7150/ijbs.85006 This issue Cite

Research Paper

XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure

Huijuan Dai1*, Xiaomei Yang2*, Xiaonan Sheng1*, Yaohui Wang1*, Shan Zhang2, Xueli Zhang2, Lipeng Hu2, Zhigang Zhang2, Xinrui Dong1, Wenjin Yin1✉, Linli Yao2✉, Jinsong Lu1✉

1. Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
2. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
* These authors contributed equally to this work.

✉ Corresponding authors: lujingsongcom (J. Lu), llyaoorg (L. Yao), and yinwenjincom (W. Yin).

Citation:
Dai H, Yang X, Sheng X, Wang Y, Zhang S, Zhang X, Hu L, Zhang Z, Dong X, Yin W, Yao L, Lu J. XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. Int J Biol Sci 2023; 19(16):5319-5336. doi:10.7150/ijbs.85006. https://www.ijbs.com/v19p5319.htm
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Abstract

Graphic abstract

Transfer RNAs (tRNAs) impact the development and progression of various cancers, but how individual tRNAs are modulated during triple-negative breast cancer (TNBC) progression remains poorly understood. Here, we found that XPOT (Exportin-T), a nuclear export protein receptor of tRNAs, is associated with poor prognosis in breast cancer and directly orchestrates the nuclear export of a subset of tRNAs, subsequently promoting protein synthesis and proliferation of human TNBC cells. XPOT knockdown inhibited TNBC cell proliferation in vitro, and RNA-seq indicated that XPOT is involved in the completion of cytokinesis in TNBC cells. High-throughput sequencing of tRNA revealed that XPOT specifically influenced a subset of tRNA isodecoders involved in nucleocytoplasmic trafficking, including tRNA-Ala-AGC-10-1. Through codon preferential analysis and protein mass spectrometry, we found that XPOT preferentially transported nuclear tRNA-Ala-AGC-10-1 to the cytoplasm, driving the translation of TPR Repeat Protein 19 (TTC19). TTC19 is also indispensable for cytokinesis and proliferation of TNBC cells. Altogether, these findings provide a novel regulatory translation mechanism for preferential tRNA isodecoder nucleocytoplasmic transport through XPOT, which coordinates the spatial location of specific tRNA and the translation of mRNA to facilitate TNBC proliferation and progression. Targeting XPOT may be a novel therapeutic strategy for treating TNBC.

Keywords: triple negative breast cancer, XPOT, tRNA nucleo-cytoplasmic transport, mRNA translation, cytokinesis

Citation styles

APA
Dai, H., Yang, X., Sheng, X., Wang, Y., Zhang, S., Zhang, X., Hu, L., Zhang, Z., Dong, X., Yin, W., Yao, L., Lu, J. (2023). XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. International Journal of Biological Sciences, 19(16), 5319-5336. https://doi.org/10.7150/ijbs.85006.

ACS
Dai, H.; Yang, X.; Sheng, X.; Wang, Y.; Zhang, S.; Zhang, X.; Hu, L.; Zhang, Z.; Dong, X.; Yin, W.; Yao, L.; Lu, J. XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. Int. J. Biol. Sci. 2023, 19 (16), 5319-5336. DOI: 10.7150/ijbs.85006.

NLM
Dai H, Yang X, Sheng X, Wang Y, Zhang S, Zhang X, Hu L, Zhang Z, Dong X, Yin W, Yao L, Lu J. XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. Int J Biol Sci 2023; 19(16):5319-5336. doi:10.7150/ijbs.85006. https://www.ijbs.com/v19p5319.htm

CSE
Dai H, Yang X, Sheng X, Wang Y, Zhang S, Zhang X, Hu L, Zhang Z, Dong X, Yin W, Yao L, Lu J. 2023. XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. Int J Biol Sci. 19(16):5319-5336.

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