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CUL4B functions as a tumor suppressor in KRAS-driven lung tumors by inhibiting the recruitment of myeloid-derived suppressor cells

Oncogene volume 42, pages 3113–3126 (2023)Cite this article

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Abstract

Lung cancer is the leading cause of cancer-related death worldwide. KRAS mutations are the most common oncogenic alterations found in lung cancer. Unfortunately, treating KRAS-mutant lung adenocarcinoma (ADC) remains a major oncotherapeutic challenge. Here, we used both autochthonous and transplantable KRAS-mutant tumor models to investigate the role of tumor-derived CUL4B in KRAS-driven lung cancers. We showed that knockout or knockdown of CUL4B promotes lung ADC growth and progression in both models. Mechanistically, CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. CUL4B deletion increases the expression of CXCL2, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration to the tumor microenvironment. Targeting of MDSCs significantly delayed the growth of CUL4B knockdown KRAS-mutant tumors. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating KRAS-driven lung tumor development.

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Fig. 1: Deletion of CUL4B accelerates KRAS-driven lung tumorigenesis.
Fig. 2: Deletion of CUL4B in Kras-mutant cancer cells promotes MDSC recruitment into the tumor microenvironment.
Fig. 3: Depletion of MDSCs blocks the enhancement of LLC tumor growth caused by CUL4B knockdown in C57 mice.
Fig. 4: Deletion of CUL4B in KRAS-mutant lung cancer cells upregulates CXCL2 expression.
Fig. 5: The enhanced MDSC recruitment by CUL4B-deficient KRAS-mutant lung cancer cells was mediated by the CXCL2-CXCR2 axis.
Fig. 6: CRL4B coordinates with HDACs to epigenetically repress Cxcl2 transcription.
Fig. 7: A schematic model of the role of CUL4B in KRAS-driven lung adenocarcinoma development.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the main text and the supplementary materials. The RNA sequencing generated in this study are publicly available in Gene Expression Omnibus at GSE222940.

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Acknowledgements

We thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work. This work was supported by the National Natural Science Foundation of China (grants 32070712 and 31671427 to YZ), China Postdoctoral Science Foundation (2022M721969 to XL and 2023M732096 to JC), the Natural Science Foundation of Shandong Province (ZR2023QH263 to XL, ZR2023QH455 to JC and ZR2020MH356 to XL), Postdoctoral Innovation Talents Support Program of Shandong Province (SDBX2022009 to JC).

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Authors and Affiliations

  1. The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

    Xiaochen Liu, Fei Tian, Li Gong, Lu Xiang, Bowen Fan, Shuangteng Liu, Jiafeng Zhan, Yadi Zhou, Baichun Jiang, Molin Wang, Gongping Sun, Yaoqin Gong & Yongxin Zou

  2. Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Xiaochen Liu

  3. Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Jianfeng Cui

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  1. Xiaochen Liu
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Contributions

YZou and YG conceived and designed the entire project. YZou and YG supervised the research conducted in their laboratories. XL, FT, JC, LX, BF, JZ and YZhou performed experiments. XL conducted all of the data analyses. XL and JC wrote the original draft. YZou, YG, BJ, MW and GS review and editing manuscript.

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Correspondence to Yaoqin Gong or Yongxin Zou.

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All mice were bred and maintained in a specific pathogen-free environment. The experimental protocol was approved by the Shandong University Animal Care Committee, and all procedures were performed in compliance with the institutional guidelines.

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Liu, X., Tian, F., Cui, J. et al. CUL4B functions as a tumor suppressor in KRAS-driven lung tumors by inhibiting the recruitment of myeloid-derived suppressor cells. Oncogene 42, 3113–3126 (2023). https://doi.org/10.1038/s41388-023-02824-1

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