BET Protein Is Involved In Regulation Of Oxidative Pentose Phosphate Pathway Through Keap1/Nrf2/G6PD Axis In Small Cell Lung Cancer

Small cell lung cancer presents as a highly proliferative and aggressive disease with rapid growth and distant metastasis.Treatment options for this recalcitrant disease have been limited.BET bromodomain inhibitor JQ1,an epigenetic agent,has shown a promising antitumor effect in a variety of cancers.The suppression of Keap1 was observed upon JQ1 treatment,further promoted the accumulation and nuclear translocation of Nrf2.The level of its downstream target genes was increased.Simultaneous application of BET inhibitor JQ1 and ATRA,an Nrf2 signaling inhibitor,have shown high synergy in a panel of SCLC cell lines,which can be rescued by NAC.Transcriptional profiling of SCLC cells based on CCLE RNA-seq dataset indicated that BRD4 expression was negatively correlated with the expression of G6PD,which encodes glucose-6-phosphate dehydrogenase.JQ1 treatment resulted in significantly increased expression of G6PD and activation of oxidative pentose phosphate pathway(PPP).Combination of G6PD inhibitor RRx-001 and JQ1 led to a synergistic inhibition on cell viability.These data established that BRD4 was a signal regulator of the cellular oxidative stress response in SCLC.Our findings provide novel insight into the transcriptional regulatory network of BRD4 and transcriptional regulation of the pentose phosphate pathway in SCLC.