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Cellular and Molecular Biology

DYNLL1 accelerates cell cycle via ILF2/CDK4 axis to promote hepatocellular carcinoma development and palbociclib sensitivity

British Journal of Cancer volume 131, pages 243–257 (2024)Cite this article

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Abstract

Background

Disorder of cell cycle represents as a major driver of hepatocarcinogenesis and constitutes an attractive therapeutic target. However, identifying key genes that respond to cell cycle-dependent treatments still facing critical challenges in hepatocellular carcinoma (HCC). Increasing evidence indicates that dynein light chain 1 (DYNLL1) is closely related to cell cycle progression and plays a critical role in tumorigenesis. In this study, we explored the role of DYNLL1 in the regulation of cell cycle progression in HCC.

Methods

We analysed clinical specimens to assess the expression and predictive value of DYNLL1 in HCC. The oncogenic role of DYNLL1 was determined by gain or loss-of-function experiments in vitro, and xenograft tumour, liver orthotopic, and DEN/CCl4-induced mouse models in vivo. Mass spectrometry analysis, RNA sequencing, co-immunoprecipitation assays, and forward and reverse experiments were performed to clarify the mechanism by which DYNLL1 activates the interleukin-2 enhancer-binding factor 2 (ILF2)/CDK4 signalling axis. Finally, the sensitivity of HCC cells to palbociclib and sorafenib was assessed by apoptosis, cell counting kit-8, and colony formation assays in vitro, and xenograft tumour models and liver orthotopic models in vivo.

Results

DYNLL1 was significantly higher in HCC tissues than that in normal liver tissues and closely related to the clinicopathological features and prognosis of patients with HCC. Importantly, DYNLL1 was identified as a novel hepatocarcinogenesis gene from both in vitro and in vivo evidence. Mechanistically, DYNLL1 could interact with ILF2 and facilitate the expression of ILF2, then ILF2 could interact with CDK4 mRNA and delay its degradation, which in turn activates downstream G1/S cell cycle target genes CDK4. Furthermore, palbociclib, a selective CDK4/6 inhibitor, represents as a promising therapeutic strategy for DYNLL1-overexpressed HCC, alone or particularly in combination with sorafenib.

Conclusions

Our work uncovers a novel function of DYNLL1 in orchestrating cell cycle to promote HCC development and suggests a potential synergy of CDK4/6 inhibitor and sorafenib for the treatment of HCC patients, especially those with increased DYNLL1.

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Fig. 1: DYNLL1 expression correlates with poor overall survival and cell cycle in patients with HCC.
Fig. 2: DYNLL1 plays an oncogenic role in HCC in vitro and vivo.
Fig. 3: ILF2 interacts with DYNLL1 protein in HCC cells.
Fig. 4: The hepatocarcinogenic function of DYNLL1 is dependent on ILF2.
Fig. 5: DYNLL1/ILF2 signalling accelerates cell cycle by activating CDK4 and stabilizing its mRNA.
Fig. 6: Palbociclib synergies with sorafenib in DYNLL1-overexpressed HCC in vitro and vivo.

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Data availability

All data needed to support the conclusions in the paper are present in the paper or the Supplementary Materials. Additional data related to this paper can be requested from the authors.

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Acknowledgements

We thank all laboratory members of the Department of Pathology of Southern Medical University for their support and comments.

Funding

This study was supported by grants from the Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer (2020B121201004); The National Natural Science Foundation of China (81972631, 82073063, 82103595, 82273039); The Natural Science Foundation of Guangdong Province (2021A1515010989, 2022A1515010298, 2022A1515111142, 2023A1515010274, 2023A1515010980); Guangdong Provincial Regional Joint Fund-Youth Fund Project (2020A1515110006); The Foundation of President of Nanfang Hospital (2020B012, 2023B005); The China Postdoctoral Science Foundation (2023M741557); Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (2020J010); The Guangdong Provincial Major Talents Project (2019JC05Y361).

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Author notes

  1. These authors contributed equally: Yuechen Liu, Zhenkang Li, Jinchao Zhang, Wei Liu.

Authors and Affiliations

  1. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China

    Yuechen Liu, Zhenkang Li, Jinchao Zhang, Wei Liu, Shenyuan Guan, Yizhi Zhan, Yongsheng Li, Haijun Deng & Zhiyong Shen

  2. Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510515, China

    Yuechen Liu, Zhenkang Li, Jinchao Zhang, Wei Liu, Shenyuan Guan, Yizhi Zhan, Yongsheng Li, Haijun Deng & Zhiyong Shen

  3. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China

    Yuan Fang

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Contributions

This study was designed by Yuechen Liu, Zhenkang Li, Zhiyong Shen, and Haijun Deng. Yuechen Liu and Zhenkang Li carried out most of the experiments and drafted the manuscript. Jinchao Zhang, Wei Liu and Shenyuan Guan performed the animal breeding and made statistical analyses. Yizhi Zhan and Yuan Fang discussed the data and drew the diagrams. Haijun Deng, Zhiyong Shen and Yongsheng Li supervised the study.

Corresponding authors

Correspondence to Yongsheng Li, Haijun Deng or Zhiyong Shen.

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The authors declare no competing interests.

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All mice care and experiments were approved by the Institutional Animal Care and Use Committee of Nanfang Hospital, and all animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals”. The use of excised human specimens was approved by the Institute Research Medical Ethics Committee of Nanfang Hospital (Guangzhou, China).

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Liu, Y., Li, Z., Zhang, J. et al. DYNLL1 accelerates cell cycle via ILF2/CDK4 axis to promote hepatocellular carcinoma development and palbociclib sensitivity. Br J Cancer 131, 243–257 (2024). https://doi.org/10.1038/s41416-024-02719-2

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