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

TL;DR

This study shows how BRD4 activates PDLIM4 to stabilize p21 and improve chemotherapy response in lung cancer, regardless of p53 status.

Contribution

The study identifies a novel p53-independent pathway involving BRD4, PDLIM4, and p21 that enhances chemosensitivity in lung adenocarcinoma.

Findings

PDLIM4 is highly expressed in LUAD and induces G2/M phase cell cycle arrest.

BRD4 activates PDLIM4 via its BD1 domain, which stabilizes p21 and inhibits cell proliferation.

Activation of the BRD4/PDLIM4/p21 pathway increases doxorubicin chemosensitivity in LUAD models.

Abstract

Understanding p53-independent regulatory mechanisms is crucial for predicting outcomes in lung adenocarcinoma (LUAD) and developing improved therapeutic strategies.

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.

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.

The online version contains supplementary material available at 10.1186/s12915-026-02511-z.

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