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

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

  • Oncogene. 2023 Aug 31. doi: 10.1038/s41388-023-02824-1.
Xiaochen Liu 1 2,  Fei Tian 1,  Jianfeng Cui 3,  Li Gong 1,  Lu Xiang 1,  Bowen Fan 1,  Shuangteng Liu 1,  Jiafeng Zhan 1,  Yadi Zhou 1,  Baichun Jiang 1,  Molin Wang 1,  Gongping Sun 1,  Yaoqin Gong 4,  Yongxin Zou 5
Affiliations

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.
  • 2 Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4 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. [email protected].
  • 5 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. [email protected].
PMID: 37653114 DOI: 10.1038/s41388-023-02824-1
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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