FBXO28 ubiquitinates BRD4 to fuel lung cancer cell malignancy

A cell-based study reports that the E3 ubiquitin ligase FBXO28 promotes malignant behavior in non-small cell lung cancer by modifying the transcriptional regulator BRD4. Researchers found that FBXO28 expression was elevated in non-small cell lung cancer samples, with higher levels associated with poorer patient outcomes. Silencing FBXO28 reduced cancer-cell proliferation, migration and invasion and increased apoptosis, whereas FBXO28 overexpression produced the opposite effects. These findings identify a molecular mechanism linked to tumor aggressiveness, but they do not establish FBXO28 or BRD4 as clinical treatment targets.

The investigators used co-immunoprecipitation assays to identify BRD4 as an FBXO28-associated protein, then examined how the two molecules regulate transcription. FBXO28 mediated ubiquitination of BRD4 at lysine 395 through a lysine 63-linked conjugation model. Unlike ubiquitination processes that direct a substrate for destruction, this modification did not cause BRD4 degradation. Instead, it enhanced BRD4 activity as a transcriptional coactivator: changing FBXO28 expression altered the abundance of BRD4-target genes and affected BRD4 binding to the promoters of those genes.

The proposed downstream mechanism involves P-TEFb, a complex associated with transcriptional elongation. FBXO28-dependent ubiquitination of BRD4 facilitated activation of P-TEFb and subsequent phosphorylation of the serine 2 residue in the C-terminal domain of the largest subunit of RNA polymerase II. This phosphorylation was linked by the researchers to the initiation of transcription. The study therefore connects a ubiquitin-signaling event to changes in transcriptional programs that support the proliferation and movement of lung cancer cells.

The authors also described a positive feedback loop. BRD4 bound to the FBXO28 promoter, and increased FBXO28 transcription further strengthened the relationship between the two proteins. The experimentally supported model is that FBXO28 ubiquitinates BRD4, activated BRD4 increases FBXO28 expression, and elevated FBXO28 can reinforce BRD4 modification and activity. Overall, the work implicates the FBXO28–BRD4 feedback loop as a contributor to non-small cell lung cancer malignancy. Because the evidence comes from patient-sample associations and functional cellular experiments, the results indicate a promising research pathway rather than demonstrating an effective intervention or clinical benefit in people with lung cancer.

Subject of Research: FBXO28-mediated BRD4 ubiquitination and transcriptional activation in non-small cell lung cancer.

Article Title: FBXO28 promotes the malignancy of non-small cell lung cancer through ubiquitination-mediated activation of BRD4

Article References: Liang, Y., Jiao, Q., Zhang, F., Bai, W., Yang, J., Luo, X., Zhang, J., Tang, X., Tang, J., Zhang, Z., Yan, J., Lai, F., Sun, L., Cao, L., Zhang, W., & Lv, X.-B. (2026). FBXO28 promotes the malignancy of non-small cell lung cancer through ubiquitination-mediated activation of BRD4. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03364-9

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03364-9

Keywords: FBXO28, BRD4, non-small cell lung cancer, ubiquitination, transcription, P-TEFb, RNA polymerase II, cancer progression, positive feedback loop, promotes, malignancy, non-small