BRD8 promotes non-small cell lung cancer progression by stabilizing MBD2 and activating the MAPK pathway.

Authors

Li Dong, Yuchen Zhou, Qingwei Cui, Zimeng Chen, Tongwei Wang, Dejun Wu, Xiaoming Lin

Published in

Cellular signalling. Pages 112704. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cases with limited therapeutic options and poor clinical outcomes. Bromodomain-containing protein 8 (BRD8), an epigenetic regulator, has been reported to exert oncogenic roles in multiple solid tumors. Nevertheless, its biological functions and molecular mechanisms in NSCLC remain largely uncharacterized, which motivates us to explore its role in NSCLC progression. The mitogen-activated protein kinase (MAPK) pathway is a well-recognized core oncogenic cascade driving NSCLC malignant phenotypes. Our transcriptome profiling further revealed that the MAPK pathway was the most significantly enriched signaling pathway downstream of BRD (Bromodomain-containing protein), thus we selected it as the key pathway for in-depth mechanistic investigation. In the present study, we found that BRD8 (Bromodomain-containing protein8) was markedly overexpressed in clinical NSCLC tissues and cell lines. Functional assays demonstrated that BRD8 prominently promoted the proliferation, migration and invasion of NSCLC cells. Co-immunoprecipitation combined with mass spectrometry confirmed the direct interaction between BRD8 and MBD2 (methyl-CpG-binding domain protein 2), and their binding was located at the methyl-CpG-binding domain of MBD2. Ubiquitination assays showed that BRD8 enhanced the total and K63 (Lysine63)-linked polyubiquitin chains of MBD2. As a typical post-translational modification, K63-linked ubiquitination generally does not trigger proteasomal degradation but maintains protein stability. Cycloheximide chase assays verified that BRD8 prolonged the half-life of MBD2 and enhanced its stability. Subsequent rescue experiments using the MBD2 K63 mutant demonstrated that mutation at this lysine residue of MBD2 abolishes BRD8-mediated assembly of K63-linked polyubiquitin chains and impairs MBD2 stability. Mechanically, MBD2 acted as a critical downstream effector to mediate BRD8-induced activation of the MAPK pathway. In vivo nude mouse xenograft experiments indicated that knockdown of BRD8 or MBD2 dramatically suppressed tumor growth and decreased MAPK pathway activity. In conclusion, BRD8 facilitates NSCLC progression by interacting with MBD2 to enhance its K63-linked ubiquitination and protein stability, thereby activating the MAPK signaling pathway. This preclinical investigation elucidates the BRD8/MBD2 oncogenic mechanism and provides evidence for subsequent NSCLC research.

PMID:
42401357
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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