Mechanistic and Therapeutic Insights for Epigenetic Regulation in Cancer Development

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in patients with Neurofibromatosis type 1 (NF1). Effective treatment options are lacking, and MPNSTs are typically fatal. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, we found that progression to MPNST and loss of MPNST relevant tumor suppressors is associated with increased levels of chromatin regulator/BET bromodomain protein BRD4, and paradoxically, sensitivity and resistance to BET bromodomain inhibition with small molecule inhibitor JQ1. Indeed, genetic and pharmacological inhibition of BRD4 profoundly suppresses both growth and tumorigenesis of MPNSTs. Mechanistically, we uncovered that BET bromodomain inhibition leads to engagement of the ER stress/UPR pathway, and apoptosis through induction of pro-apoptotic effector molecule BIM and suppression of anti-apoptotic BCL-2 in MPNSTs. Moreover, we find that suppressed transcription of Cyclin D1 oncogene upon BRD4 inhibition correlates with reduced proliferation of MPNSTs. All together, this dual restraint on proliferation (via Cyclin D1 downregulation) and survival (via BIM induction) may indicate how BRD4 inhibition is exquisitely effective against MPNSTs and may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate an epigenetic mechanism underlying the balance of anti-/pro-apoptotic molecules, which suggests that BET bromodomain inhibition can shift this balance in favor of cancer cell death. Collectively, these studies provide new insights for developing strategies to overcome resistance to BET bromodomain inhibitor therapy for subverting cancer cell survival.