Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma

Abstract

Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.

The PI3K Pathway in Human Disease

“…BRD4 functions as an epigenetic reader that recognizes histones bearing acetylated lysine residues, and plays a key role in the regulation of transcriptionally-active chromatin. Inhibitors of BRD4 suppress the expression of super-enhancer-associated genes such as MYC (Delmore et al, 2011; Mertz et al, 2011; Zuber et al, 2011), and small molecule BET inhibitors are known to interfere with c-MYC-dependent transcriptional responses (Venkataraman et al, 2014). In ER+ breast cancer cells, BET inhibitors also overcame resistance to everolimus caused by c-Myc overexpression (Bihani et al, 2015), and exerted synergistic antitumor activity with PI3K inhibitors in mice with mammary tumors initiated by oncogenic PI3K-H1047R plus MYC transgene expression (Stratikopoulos et al, 2015).…”

Molecular mechanisms and therapeutic targets in pediatric brain tumors

“…Treatment of MYCamplified human and mouse MBs with the bromodomain inhibitor JQ1 arrested cell cycle at the G 1 stage, induced apoptosis, and prolonged survival of tumor-bearing mice (67). Bromodomain inhibitors are currently in trials for other cancers and, based on their activity in preclinical models of both SHH-MB and G3-MB (67,68,89), are being considered for treatment of MB as well.…”

In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment

“…In the last years, studies have explored the antitumor effect of agents that inhibit the bromodomain and extraterminal (BET) family of bromodomain-containing proteins (9,10). An example is the antitumor effect of these agents in several cancers such as neuroblastoma by reducing the expression of oncogenic transcription factors like cmyc, among others (10)(11)(12)(13)(14). These findings suggest that transcription factors are indirectly druggable, opening new avenues for targeting diseases where upregulation of these proteins may facilitate malignant transformation.…”