MYC: connecting selective transcriptional control to global RNA production

Kress, Theresia R.; Sabò, Arianna; Amati, Bruno

doi:10.1038/nrc3984

Cited by 432 publications

(446 citation statements)

References 196 publications

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“…promoters with an open chromatin structure as well as to thousands of enhancers together with an obligate heterodimerization partner, MAX (for recent reviews, see: [1][2][3] ). They can both activate and repress genes transcribed by RNA polymerase II and, in some circumstances, enhance expression of all genes.…”

Section: Introductionmentioning

confidence: 99%

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

et al. 2016

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Section: Introductionmentioning

confidence: 99%

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

et al. 2016

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“…It encodes a transcription factor that binds to and regulates nearly 10-15% of genes in the human genome (1)(2)(3). The MYC targets mediate fundamental biological processes necessary for cell survival and general well-being, ranging from gene-expression and cell-cycle programs to cell proliferation and response to DNA damage, thereby establishing MYC as a global transcriptional regulator.…”

mentioning

confidence: 99%

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Andrews

Singh

Joshi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

118

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MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dualactivity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.T he MYC gene is frequently altered in human cancer. It encodes a transcription factor that binds to and regulates nearly 10-15% of genes in the human genome (1-3). The MYC targets mediate fundamental biological processes necessary for cell survival and general well-being, ranging from gene-expression and cell-cycle programs to cell proliferation and response to DNA damage, thereby establishing MYC as a global transcriptional regulator. MYC is overexpressed or amplified in many human cancers, which results in genome instability and deregulation of an array of signaling pathways responsible for malignant transformation. MYC expression level as well as synthesis, stability, and posttranslational modifications (PTMs) of the MYC protein are tightly regulated via several pathways, including PI3K-AKTmTOR and RAS-MAPK (4). Particularly, PI3K activation blocks MYC degradation through inhibiting GSK3β-dependent MYC phosphorylation at threonine 58, elevating MYC levels and inducing MYC-dependent oncogenic programs (4, 5).MYC gene expression has recently been linked to the activity of the BET (bromodomains and extraterminal domain) family of transcriptional coactivators (6-9). The BET protein BRD4 is found enriched at MYC and other oncogenes superenhancer and promoter regions, and transcriptional silencing of MYC coincides with the release of BET proteins from its locus, indicating that BET proteins can regulate MYC expression (10, 11). BRD4 itself is linked to multiple human malignancies: It forms chromosomal translocations in squamous carcinoma and NUT midline carcinoma, plays a role in progression of acute myeloid leukemia, and is up-regulated in breast cancer (7,(12)(13)(14). BRD4 contains a pair of bromodomains (BDs) that belong to the family of evolutionarily conserved structural modules that recognize acetyllysine PTMs in histones and nonhistone proteins (15, 16). Interestingly, BD1 and BD2 of BRD4 have distinct acetyllysine binding functions (17). BD1 binds to diacetylated histones, including histone H4 diacetylated at lysine 5 and lysine 8 (H4K5acK8ac), and this interaction helps to recruit or stabilize BRD4-containing transcription complexes at target gene promoters and enhancers. The se...

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“…There is evidence that MYC can act as a direct or indirect general amplifier of a pre-existent and contextspecific oncogenic genetic network (40). MYC-dependent transcription needs the assembly of multiprotein complexes.…”

Section: Targeting Myc Indirectlymentioning

confidence: 99%

“…MYC recruitment to DNA is controlled by mechanisms beyond MYC/MAX dimerization (40). Therefore, such molecular processes also offer the opportunity to target MYC.…”

Section: Targeting Myc Directlymentioning

confidence: 99%

Concepts to Target MYC in Pancreatic Cancer

Wirth

Mahboobi

Krämer

et al. 2016

Molecular Cancer Therapeutics

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Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC.

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MYC: connecting selective transcriptional control to global RNA production

Cited by 432 publications

References 196 publications

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Concepts to Target MYC in Pancreatic Cancer

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