gsk1210151a and Carcinoma--Non-Small-Cell-Lung

The bromodomain and extra‑terminal domain (BET) family proteins are essential epigenetic regulators in lung cancer. However, BET inhibitors have not had the anticipated therapeutic efficacy. Combined treatment using BET inhibitors along with other drugs had favorable therapeutic effects but the underlying molecular mechanisms remain elusive. The aim of the present study was to investigate the antineoplastic effects and mechanisms of a combination of a BET inhibitor and paclitaxel or cisplatin in non‑small cell lung cancer (NSCLC). By using the online Kaplan‑Meier plotter, it was revealed that increased mRNA levels of several BET protein‑coding genes were associated with poor prognosis in NSCLC. SRB assay results revealed that pharmaceutical or genetic targeting of BET proteins suppressed the growth of NSCLC cells. Inhibition of BET protein expression, in combination with the use of chemotherapeutic drugs such as paclitaxel and cisplatin, further restrained NSCLC cell growth in a synergistic manner. Mechanistically, this combination of suppression of BET expression and chemotherapeutic treatment blocked NSCLC cell growth by inhibiting autophagy and promoting apoptosis, which were revealed by both western blot and ELISA results. The present findings revealed a new rationale for using a combination of BET inhibitors with chemotherapy in NSCLC treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azepines; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Heterocyclic Compounds, 4 or More Rings; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Paclitaxel; Prognosis; Signal Transduction; Transcription Factors; Triazoles

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.

Topics: A549 Cells; Animals; Azepines; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Eukaryotic Initiation Factor-4E; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Mice; Mice, Nude; Molecular Targeted Therapy; Nuclear Proteins; Random Allocation; Transcription Factors; Transfection; Triazoles; Xenograft Model Antitumor Assays