BRD4 Sustains Melanoma Proliferation and Represents a New Target for Epigenetic Therapy

Abstract

Metastatic melanoma remains a mostly incurable disease. Although newly approved targeted therapies are efficacious in a subset of patients, resistance and relapse rapidly ensue. Alternative therapeutic strategies to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell identity are emerging. Bromodomain and extraterminal domain (BET) proteins are epigenome readers known to exert key roles at the interface between chromatin remodeling and transcriptional regulation. Here, we report that BRD4, a BET family member, is significantly upregulated in primary and metastatic melanoma tissues compared with melanocytes and nevi. Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor–treated cells followed by Gene Ontology analysis showed a striking impact on transcriptional programs controlling cell growth, proliferation, cell-cycle regulation, and differentiation. In particular, we found that, rapidly after BET displacement, key cell-cycle genes (SKP2, ERK1, and c-MYC) were downregulated concomitantly with the accumulation of cyclin-dependent kinase (CDK) inhibitors (p21 and p27), followed by cell-cycle arrest. Importantly, BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status, opening the possibility of using these small-molecule compounds to treat patients for whom no effective targeted therapy exists. Collectively, our study reveals a critical role for BRD4 in melanoma tumor maintenance and renders it a legitimate and novel target for epigenetic therapy directed against the core transcriptional program of melanoma.

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

“…To assess whether RVX2135 affects cell types other than Myc-induced lymphoma, we cultured five melanoma cell lines in the absence or presence of 10 μM RVX2135. Similar to previous studies on a different BET inhibitor (18), RVX2135 suppressed cell-cycle progression (Fig. S3A).…”

“…The in vivo data presented here and previous studies using other BETi have shown that inhibition of BET proteins is tolerated in mice (3,18,44,45). BETi exhibit broad transcriptional effects by targeting the general transcriptional elongation factor p-TEFb's interplay with Brd4.…”

BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway

“…Previous studies have demonstrated that BRD4 promotes cell cycle progression and regulates cell growth and transcription (13). Subsequent studies have demonstrated that BRD4 serves a critical role in tumor proliferation and growth in melanoma (14), neuroblastoma (15), glioblastoma (16), malignant peripheral nerve sheath tumors (17), lymphoblastic leukemia (18) and lung adenocarcinoma (19). However, to the best of our knowledge, the involvement of BRD4 in migration and invasion has not been reported in HCC.…”

Histone variant H2A.Z.2: A novel driver of melanoma progression

“…Based on our observation that H2A.Z.2 loss has a dramatic effect on histone acetylation and BRD2 cellular levels, we queried whether its deficiency could cooperate with BET inhibition. 9 Intriguingly, whereas in control cells the BET inhibitor JQ1 10 exerts a cytostatic effect, cells depleted of H2A.Z.2 that are treated with the same doses of JQ1 die by apoptosis. In addition, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and to MEK inhibitors.…”