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

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 challenge in cancer treatment of directly inhibiting the KRAS oncoprotein, indicating the need for understanding the regulatory mechanism with this molecular profile. 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 show that knockout or knockdown of CUL4B promotes lung adenocarcinoma growth and progression in both two 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, and in turn, suppresses anti-tumor immunity. Targeting MDSCs with anti-Gr-1 neutralizing antibody or treatment with CXCR2 antagonist SB265610 significantly suppresses MDSCs infiltration and delayed the growth of CUL4B knockdown KRAS mutant lung adenocarcinoma tumors. Moreover, a negative correlation between CUL4B and CXCL2 expression was observed in high-stage KRAS mutant lung ADC patients. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating the KRAS-driven lung tumor development.

ORGANISM(S): Mus musculus

PROVIDER: GSE222940 | GEO | 2026/01/15

REPOSITORIES: GEO

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