MYC protein stability is negatively regulated by BRD4

Abstract

<jats:p>The protooncogene MYC regulates a variety of cellular processes, including proliferation and metabolism. Maintaining MYC at homeostatic levels is critical to normal cell function; overexpression drives many cancers. MYC stability is regulated through phosphorylation: phosphorylation at Thr58 signals degradation while Ser62 phosphorylation leads to its stabilization and functional activation. The bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator with intrinsic kinase and histone acetyltransferase (HAT) activities that activates transcription of key protooncogenes, including<jats:italic>MYC</jats:italic>. We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. Importantly, BRD4 degradation, but not inhibition, results in increased levels of MYC protein. Conversely, MYC inhibits BRD4’s HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. These findings demonstrate that BRD4 negatively regulates MYC levels, which is counteracted by ERK1 activation.</jats:p>

Chromosome 8 gain is associated with high-grade transformation in MPNST

“…Reuss and colleagues (34) showed that MPNST cell lines with complete NF1 deficiency were sensitive to TRAIL-induced cell death that was critically dependent on c-myc . Thus, targeting dysregulated c-myc expression using BRD4 inhibitors may represent a therapeutic opportunity in NF1-associated MPNST (35). There are several other cancer-related genes on Chr8q including UBR5 and RAD21 , and we continue to investigate their potential role in MPNST tumorigenesis.…”

BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors

“…Dysfunction of BET proteins has been strongly linked to the development and progression of various tumors (3). Specifically, BRD4 acts as a synthetic lethal factor of the proto-oncogene MYC, in which BRD4 not only promotes MYC transcription but also regulates its function and degradation (4,5). Given the essential role of BET family proteins in cancer development and inflammation, more than 100 clinical trials are now being carried out to evaluate the benefits of BET inhibitors (BETi) as anticancer therapy (6).…”

The Molecular ‘Myc-anisms’ behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics

“…First, BET proteins are known to regulate MYC transcription [ 51 ]. A recent study demonstrated in normal cells that BRD4 has even more control over Myc by binding and phosphorylating Threonine 58 on Myc, leading to degradation [ 52 ]. However, Myc is also capable of regulating BRD4′s histone acetyl transferase activity [ 52 ].…”

“…A recent study demonstrated in normal cells that BRD4 has even more control over Myc by binding and phosphorylating Threonine 58 on Myc, leading to degradation [ 52 ]. However, Myc is also capable of regulating BRD4′s histone acetyl transferase activity [ 52 ]. Additional studies are needed to better understand how this circular balance may be affected in cancer.…”

“…Devaiah et al recently discovered crucial molecular differences in Myc stability between BET inhibitors and BET degraders. Since endogenous BRD4 destabilizes Myc, treatment with a BRD4 degrader, such as MZ1, enhances Myc stability, but treatment with a BET inhibitor, such as JQ1, does not affect BRD4′s phosphorylation of Myc and therefore Myc’s half-life is unaffected while MYC transcription is downregulated [ 52 ]. Several PROTAC BRD4 degraders demonstrate robust decreases of MYC expression throughout 3–24 h [ 79 , 80 ], though there are no current clinical trials on BET/BRD4 degraders.…”