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DHX9 contributes to the malignant phenotypes of colorectal cancer via activating NF-κB signaling pathway

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Abstract

Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide, which makes it urgent to identify novel therapeutic targets for CRC treatment. In this study, DHX9 was filtered out as the prominent proliferation promoters of CRC by siRNA screening. Moreover, DHX9 was overexpressed in CRC cell lines, clinical CRC tissues and colitis-associated colorectal cancer (CAC) mouse model. The upregulation of DHX9 was positively correlated with poor prognosis in patients with CRC. Through gain- and loss-of function experiments, we found that DHX9 promoted CRC cell proliferation, colony formation, apoptosis resistance, migration and invasion in vitro. Furthermore, a xenograft mouse model and a hepatic metastasis mouse model were utilized to confirm that forced overexpression of DHX9 enhanced CRC outgrowth and metastasis in vivo, while DHX9 ablation produced the opposite effect. Mechanistically, from one aspect, DHX9 enhances p65 phosphorylation, promotes p65 nuclear translocation to facilitate NF-κB-mediated transcriptional activity. From another aspect, DHX9 interacts with p65 and RNA polymerase II (RNA Pol II) to enhance the downstream targets of NF-κB (e.g., Survivin, Snail) expression to potentiate the malignant phenotypes of CRC. Together, our results suggest that DHX9 may be a potential therapeutic target for prevention and treatment of CRC patients.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author (Zhiping.Liu@gmu.edu.cn) on reasonable request.

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Acknowledgements

This work was supported by funds from National Natural Science Foundation of China (31560260 and 31960163 to Zhiping Liu, Youth Project 82003801 to Shenglan Liu), The Jinggang Scholar Program in Jiangxi Province (to Zhiping Liu), Natural Science Foundation of Jiangxi Province (20171ACB20024 and 20181BAB205032 to Zhiping Liu) and Technological Innovation Team Project of Gannan Medical University (TD201703 to Zhiping Liu).

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Authors and Affiliations

  1. College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi, China

    Shenglan Liu & Wei Dai

  2. Department of Gastroenterology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China

    Liangmei He

  3. Gannan Medical University, Ganzhou, Jiangxi, China

    Junhong Wu & Xinqiang Wu

  4. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Xinqiang Wu

  5. School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Lu Xie, Lingxia Chen, Fuhua Xie & Zhiping Liu

  6. Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China

    Zhiping Liu

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  1. Shenglan Liu
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Contributions

ZL and FX developed the hypothesis, designed, guided research, and revised manuscript. SL performed the experiments, analyzed data, and wrote the manuscript. LH performed the experiments and analyzed data. JW, XW, LX, WD and LC assisted the experiments. All authors read and approved the final manuscript.

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Correspondence to Fuhua Xie or Zhiping Liu.

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Liu, S., He, L., Wu, J. et al. DHX9 contributes to the malignant phenotypes of colorectal cancer via activating NF-κB signaling pathway. Cell. Mol. Life Sci. 78, 8261–8281 (2021). https://doi.org/10.1007/s00018-021-04013-3

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