Journal Article

BRD4-mediated transcriptional activation of PDLIM4 enhances p21 stability and chemosensitivity in lung adenocarcinoma independent of p53

Shu, Tao, Luo, Lianxiang, Wang, Qingwei, Gao, Xiao, Guo, Liangsheng, Wang, Shuai, Zheng, Lei, Guan, Chengdan, Gu, Yonghui, Lai, Tianwen, Pan, Junhao, Zhu, Shaoping, Wu, Xuehua

2026

Overview

Background Understanding p53-independent regulatory mechanisms is crucial for predicting outcomes in lung adenocarcinoma (LUAD) and developing improved therapeutic strategies. Results We found that PDLIM4 is highly expressed in LUAD tumor tissues, where it induces G2/M phase cell cycle arrest and suppresses cell proliferation, suggesting its potential role in improving patient prognosis. Our study identified BRD4, a bromodomain and extraterminal (BET) family protein, as a key transcriptional regulator of PDLIM4, acting through its BD1 domain. Further analysis revealed that wild-type PDLIM4 stabilizes p21 by blocking its RNA degradation, leading to p21 protein accumulation and subsequent inhibition of cell proliferation. In contrast, the S116 mutation in PDLIM4 abrogates this regulatory effect. Notably, activation of the BRD4/PDLIM4/p21 pathway enhanced chemosensitivity to doxorubicin in both LUAD cells and xenograft tumor models. Conclusions Given the high mutation frequency of PDLIM4 recorded in the TCGA cancer database, our findings reveal a critical regulatory signaling pathway that suppresses LUAD progression and augments chemotherapy efficacy.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - drug therapy / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - metabolism / Animals / Biomedical and Life Sciences / BRD4 / Bromodomain Containing Proteins / Cell culture / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell growth / Cell Line, Tumor / Cell proliferation / Chemotherapy / Cloning / Colorectal cancer / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Doxorubicin / Gene Expression Regulation, Neoplastic / Genes / GTP-binding protein / Humans / Kinases / Life Sciences / LIM Domain Proteins - genetics / LIM Domain Proteins - metabolism / Lung adenocarcinoma / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lungs / Medical prognosis / Mice / Mutation / Ovarian cancer / P21 / P53 independent / p53 Protein / PDLIM4 / Prostate cancer / Proteins / Regulatory mechanisms (biology) / Signal transduction / Transcription activation / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Activation / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors / Xenotransplantation