Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression

ABSTRACT

Lung cancer is the leading cause of cancer-related death worldwide. Bromodomain and extraterminal domain (BET) proteins act as epigenome readers for gene transcriptional regulation. Among BET family members, BRD4 was well studied, but for its mechanism in non-small cell lung carcinoma has not been elucidated. eIF4E regulates gene translation and has been proved to play an important role in the progression of lung cancer. In this study, we first confirmed that BET inhibitors JQ1 and I-BET151 suppressed the growth of NSCLCs, in parallel with downregulated eIF4E expression. Then we found that knockdown of BRD4 expression using siRNAs inhibited the growth of NSCLCs as well as decreased eIF4E protein levels. Moreover, overexpression of eIF4E partially abrogated the growth inhibitory effect of JQ1, while knockdown of eIF4E enhanced the inhibitory effect of JQ1. Furthermore, JQ1 treatment or knockdown of BRD4 expression decreased eIF4E mRNA levels and inhibited its promoter activity by luciferase reporter assay. JQ1 treatment significantly decreased the binding of eIF4E promoter with BRD4. Finally, JQ1 inhibited the growth of H460 tumors in parallel with downregulated eIF4E mRNA and protein levels in a xenograft mouse model. These findings suggest that inhibition of BET by JQ1, I-BET151, or BRD4 silencing suppresses the growth of non-small cell lung carcinoma through decreasing eIF4E transcription and subsequent mRNA and protein expression. Considering that BET regulates gene transcription epigenetically, our findings not only reveal a new mechanism of BET-regulated eIF4E in lung cancer, but also indicate a novel strategy by co-targeting eIF4E for enhancing BET-targeted cancer therapy.

KEYWORDS:

• BRD4
• eIF4E
• non-small cell lung carcinoma
• epigenetics
• molecular targeted therapy

Disclosure statement

No conflicts of interest.

Acknowledgments

This work is supported by the National Natural Science Foundation of China under Grant No. 81102458, 81473241, 81172004 for X, Wang; No. 81372395 for Z, Cheng; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China, 210029 (X, Wang); and Six Talents Peak Project of Jiangsu Province (No.2013-WSN-048) (Z, Cheng). We thank Dr. Shi-Yong Sun in Emory University for providing p3 × flag-eIF4E overexpression plasmid and pGL3-eIF4E promoter plasmid. We thank Dr. Jialiang Wang in Vanderbilt University for discussion.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (NSFC)(81102458), National Natural Science Foundation of China (NSFC)(81372395), National Natural Science Foundation of China (NSFC)(81172004), National Natural Science Foundation of China (NSFC)(81473241).