Abstract
The transcription factor and oncoprotein MYC is a potent driver of many human cancers and can regulate numerous biological activities that contribute to tumorigenesis. How a single transcription factor can regulate such a diverse set of biological programmes is central to the understanding of MYC function in cancer. In this Perspective, we highlight how multiple proteins that interact with MYC enable MYC to regulate several central control points of gene transcription. These include promoter binding, epigenetic modifications, initiation, elongation and post-transcriptional processes. Evidence shows that a combination of multiple protein interactions enables MYC to function as a potent oncoprotein, working together in a ‘coalition model’, as presented here. Moreover, as MYC depends on its protein interactome for function, we discuss recent research that emphasizes an unprecedented opportunity to target protein interactors to directly impede MYC oncogenesis.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976–990 (2008).
Kalkat, M. et al. MYC deregulation in primary human cancers. Genes 8, 2–30 (2017).
Dang, C. V., Reddy, E. P., Shokat, K. M. & Soucek, L. Drugging the “undruggable” cancer targets. Nat. Rev. Cancer 17, 502–508 (2017).
Patel, J. H., Loboda, A. P., Showe, M. K., Showe, L. C. & McMahon, S. B. Analysis of genomic targets reveals complex functions of MYC. Nat. Rev. Cancer 4, 562–568 (2004).
Lin, C. Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012).
Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).
Tansey, W. P. Mammalian MYC proteins and cancer. N. J. Sci. 2014, 1–27 (2014).
SC, C. et al. The MYC oncogene is a global regulator of the immune response. Blood 131, 2007–2015 (2018).
Di Giacomo, S., Sollazzo, M., Paglia, S. & Grifoni, D. MYC, cell competition, and cell death in cancer: the inseparable triad. Genes 8, 120 (2017).
Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC, metabolism, and cancer. Cancer Discov. 5, 1024–1039 (2015).
Yoshida, G. J. Emerging roles of Myc in stem cell biology and novel tumor therapies. J. Exp. Clin. Cancer Res. 37, 173 (2018).
Dang, C. V. et al. The c-Myc target gene network. Semin. Cancer Biol. 16, 253–264 (2006).
Baluapuri, A., Wolf, E. & Eilers, M. Target gene-independent functions of MYC oncoproteins. Nat. Rev. Mol. Cell Biol. 21, 255–267 (2020).
Wolf, E., Lin, C. Y., Eilers, M. & Levens, D. L. Taming of the beast: shaping Myc-dependent amplification. Trends Cell Biol. 25, 241–248 (2015).
Nie, Z. et al. Dissecting transcriptional amplification by MYC. eLife 9, e52483 (2020).
Richards, M. W. et al. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc. Natl Acad. Sci. USA 113, 13726–13731 (2016).
Nair, S. K. & Burley, S. K. X-ray structures of Myc-max and mad-max recognizing DNA. Cell 112, 193–205 (2003).
Thomas, L. R. et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol. Cell 58, 440–452 (2015).
Wei, Y. et al. Multiple direct interactions of TBP with the MYC oncoprotein. Nat. Struct. Mol. Biol. 26, 1035–1043 (2019).
Pineda-Lucena, A. et al. A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants. J. Mol. Biol. 351, 182–194 (2005).
Andresen, C. et al. Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding. Nucleic Acids Res. 40, 6353–6366 (2012).
Bayliss, R., Burgess, S. G., Leen, E. & Richards, M. W. A moving target: structure and disorder in pursuit of Myc inhibitors. Biochem. Soc. Trans. 45, 709–717 (2017).
Blackwood, E. & Eisenman, R. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251, 1211–1217 (1991).
Amati, B. et al. Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell 72, 233–245 (1993).
Helander, S. et al. Pre-anchoring of Pin1 to unphosphorylated c-Myc in a fuzzy complex regulates c-Myc activity. Structure 23, 2267–2279 (2015).
Guarnaccia, A. & Tansey, W. Moonlighting with WDR5: a cellular multitasker. J. Clin. Med. 7, 21 (2018).
Carugo, A. et al. In vivo functional platform targeting patient-derived xenografts identifies WDR5-Myc association as a critical determinant of pancreatic cancer. Cell Rep. 16, 133–147 (2016).
Sun, Y. et al. WDR5 supports an N-Myc transcriptional complex that drives a protumorigenic gene expression signature in neuroblastoma. Cancer Res. 75, 5143–5154 (2015).
Thomas, L. R. et al. Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance. Proc. Natl Acad. Sci. USA 116, 25260–25268 (2019).
Dingar, D. et al. MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability. Nat. Commun. 9, 3502 (2018).
Richart, L. et al. BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis. Nat. Commun. 7, 10153 (2016).
Weissmiller, A. M. et al. Inhibition of MYC by the SMARCB1 tumor suppressor. Nat. Commun. 10, 2014 (2019).
Stojanova, A. et al. MYC interaction with the tumor suppressive SWI/SNF complex member INI1 regulates transcription and cellular transformation. Cell Cycle 15, 1693–1705 (2016).
Carroll, P. A., Freie, B. W., Mathsyaraja, H. & Eisenman, R. N. The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis. Front. Med. 12, 412–425 (2018).
McMahon, S. B., Van Buskirk, H. A., Dugan, K. A., Copeland, T. D. & Cole, M. D. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94, 363–374 (1998).
Doyon, Y., Selleck, W., Lane, W. S., Tan, S. & Côté, J. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Mol. Cell. Biol. 24, 1884–1896 (2004).
McMahon, S. B., Wood, M. A. & Cole, M. D. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol. Cell. Biol. 20, 556–562 (2000).
Frank, S. R. et al. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep. 4, 575–580 (2003).
Knoepfler, P. S. et al. Myc influences global chromatin structure. EMBO J. 25, 2723–2734 (2006).
Kalkat, M. et al. MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis. Mol. Cell 72, 836–848.e7 (2018).
Ullius, A. et al. The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification. Nucleic Acids Res. 42, 6901–6920 (2014).
Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).
Liang, G. et al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc. Natl Acad. Sci. USA 101, 7357–7362 (2004).
Zhang, N. et al. MYC interacts with the human STAGA coactivator complex via multivalent contacts with the GCN5 and TRRAP subunits. Biochim. Biophys. Acta Gene Regul. Mech. 1839, 395–405 (2014).
Vervoorts, J. et al. Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep. 4, 484–490 (2003).
Martinato, F., Cesaroni, M., Amati, B. & Guccione, E. Analysis of Myc-induced histone modifications on target chromatin. PLoS ONE 3, e3650 (2008).
Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011).
Tikhanovich, I. et al. Arginine methylation regulates c-Myc–dependent transcription by altering promoter recruitment of the acetyltransferase p300. J. Biol. Chem. 292, 13333–13344 (2017).
Zargar, Z. U. & Tyagi, S. Role of host cell factor-1 in cell cycle regulation. Transcription 3, 187–192 (2012).
Lundberg, S. M. et al. ChromNet: learning the human chromatin network from all ENCODE ChIP-seq data. Genome Biol. 17, 82 (2016).
Thomas, L. R. et al. Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif. Oncogene 35, 3613–3618 (2016).
Popay, T. M. et al. MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor–1. eLife 10, e60191 (2021).
Oskarsson, T. & Trumpp, A. The Myc trilogy: lord of RNA polymerases. Nat. Cell Biol. 7, 215–217 (2005).
Engel, C., Neyer, S. & Cramer, P. Distinct mechanisms of transcription initiation by RNA polymerases I and II. Annu. Rev. Biophys. 47, 425–446 (2018).
Gomez-Roman, N. et al. Activation by c-Myc of transcription by RNA polymerases I, II and III. Biochem. Soc. Symp. 73, 141–154 (2006).
Campbell, K. J. & White, R. J. MYC regulation of cell growth through control of transcription by RNA polymerases I and III. Cold Spring Harb. Perspect. Med. 4, a018408–a018408 (2014).
Nogales, E., Louder, R. K. & He, Y. Cryo-EM in the study of challenging systems: the human transcription pre-initiation complex. Curr. Opin. Struct. Biol. 40, 120–127 (2016).
Gupta, K., Sari-Ak, D., Haffke, M., Trowitzsch, S. & Berger, I. Zooming in on transcription preinitiation. J. Mol. Biol. 428, 2581–2591 (2016).
Greber, B. J. & Nogales, E. The structures of eukaryotic transcription pre-initiation complexes and their functional implications. Subcell. Biochem. https://doi.org/10.1007/978-3-030-28151-9_5 (2019).
Hateboer, G. et al. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc. Natl Acad. Sci. USA 90, 8489–8493 (1993).
Maheswaran, S., Lee, H. & Sonenshein, G. E. Intracellular association of the protein product of the c-myc oncogene with the TATA-binding protein. Mol. Cell. Biol. 14, 1147–1152 (1994).
McEwan, I. J., Dahlman-Wright, K., Ford, J. & Wright, A. P. H. Functional interaction of the c-Myc transactivation domain with the TATA binding protein: evidence for an induced fit model of transactivation domain folding. Biochemistry 35, 9584–9593 (1996).
Core, L. J. & Adelman, K. Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation. Genes Dev. 33, 960–982 (2019).
Fuda, N. J., Ardehali, M. B. & Lis, J. T. Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461, 186–192 (2009).
Glover-Cutter, K. et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol. Cell. Biol. 29, 5455–5464 (2009).
Cowling, V. H. & Cole, M. D. The Myc transactivation domain promotes global phosphorylation of the RNA polymerase II carboxy-terminal domain independently of direct DNA binding. Mol. Cell. Biol. 27, 2059–2073 (2007).
Posternak, V., Ung, M. H., Cheng, C. & Cole, M. D. MYC mediates mRNA cap methylation of canonical Wnt/β-catenin signaling transcripts by recruiting CDK7 and RNA methyltransferase. Mol. Cancer Res. 15, 213–224 (2017).
Jonkers, I. & Lis, J. T. Getting up to speed with transcription elongation by RNA polymerase II. Nat. Rev. Mol. Cell Biol. 16, 167–177 (2015).
Rasmussen, E. B. & Lis, J. T. In vivo transcriptional pausing and cap formation on three Drosophila heat shock genes. Proc. Natl Acad. Sci. USA 90, 7923–7927 (1993).
Bentley, D. L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15, 163–175 (2014).
Lombardi, O., Varshney, D., Phillips, N. M. & Cowling, V. H. c-Myc deregulation induces mRNA capping enzyme dependency. Oncotarget 7, 82273–82288 (2016).
Cole, M. D. & Cowling, V. H. Specific regulation of mRNA cap methylation by the c-Myc and E2F1 transcription factors. Oncogene 28, 1169–1175 (2009).
Cowling, V. H. Enhanced mRNA cap methylation increases cyclin D1 expression and promotes cell transformation. Oncogene 29, 930–936 (2010).
Eberhardy, S. R. & Farnham, P. J. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J. Biol. Chem. 277, 40156–40162 (2002).
Kanazawa, S., Soucek, L., Evan, G., Okamoto, T. & Peterlin, B. M. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis. Oncogene 22, 5707–5711 (2003).
Eberhardy, S. R. & Farnham, P. J. c-Myc mediates activation of the cad promoter via a Post-RNA polymerase II recruitment mechanism. J. Biol. Chem. 276, 48562–48571 (2001).
Gargano, B., Amente, S., Majello, B. & Lania, L. P-TEFb is a crucial co-factor for Myc transactivation. Cell Cycle 6, 2031–2037 (2007).
Rahl, P. B. et al. C-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).
Jang, M. K. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523–534 (2005).
Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535–545 (2005).
Liang, K. et al. Targeting processive transcription elongation via SEC disruption for MYC-induced cancer therapy. Cell 175, 766–779.e17 (2018).
Baluapuri, A. et al. MYC recruits SPT5 to RNA polymerase II to promote processive transcription elongation. Mol. Cell 74, 674–687.e11 (2019).
Bywater, M. J. et al. Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity. Nat. Commun. 11, 1827 (2020).
Cossa, G. et al. Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription. Mol. Cell 77, 1322–1339.e11 (2020).
Cortazar, M. A. et al. Control of RNA Pol II speed by PNUTS-PP1 and Spt5 dephosphorylation facilitates termination by a “sitting duck torpedo” mechanism. Mol. Cell 76, 896–908.e4 (2019).
Jerebtsova, M. et al. Mass spectrometry and biochemical analysis of RNA polymerase II: Targeting by protein phosphatase-1. Mol. Cell. Biochem. 347, 79–87 (2011).
Washington, K. et al. Protein phosphatase-1 dephosphorylates the C-terminal domain of RNA polymerase-II. J. Biol. Chem. 277, 40442–40448 (2002).
Staller, P. et al. Repression of p15INK4b expression by Myc through association with Miz-1. Nat. Cell Biol. 3, 392–399 (2001).
Gartel, A. L. & Shchors, K. Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp. Cell Res. 283, 17–21 (2003).
Marhin, W. W., Chen, S., Facchini, L. M., Fornace Jr, A. J. & Penn, L. Z. Myc represses the growth arrest gene gadd45. Oncogene 14, 2825–2834 (1997).
Gartel, A. L. et al. Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc. Natl Acad. Sci. USA 98, 4510–4515 (2001).
Wanzel, M., Herold, S. & Eilers, M. Transcriptional repression by Myc. Trends Cell Biol. 13, 146–150 (2003).
Molander, C., Hackzell, A., Ohta, M., Izumi, H. & Funa, K. Sp1 is a key regulator of the PDGF beta-receptor transcription. Mol. Biol. Rep. 28, 223–233 (2001).
Gherardi, S., Valli, E., Erriquez, D. & Perini, G. MYCN-mediated transcriptional repression in neuroblastoma: the other side of the coin. Front. Oncol. 3, 42 (2013).
Kurland, J. F. & Tansey, W. P. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 68, 3624–3629 (2008).
Zhang, X. et al. Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31, 3002–3008 (2012).
Tu, W. B. et al. MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis. Cancer Cell 34, 579–595.e8 (2018).
Moore, J. P., Hancock, D. C., Littlewood, T. D. & Evan, G. I. A sensitive and quantitative enzyme-linked immunosorbence assay for the c-myc and N-myc oncoproteins. Oncogene Res. 2, 65–80 (1987).
Boija, A. et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175, 1842–1855.e16 (2018).
Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).
Lu, H. et al. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature 558, 318–323 (2018).
Guo, C. et al. ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation. Sci. Adv. 6, eaay4858 (2020).
Guo, Y. E. et al. Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature 572, 543–548 (2019).
Zamudio, A. V. et al. Mediator condensates localize signaling factors to key cell identity genes. Mol. Cell 76, 753–766.e6 (2019).
Guo, J. et al. Sequence specificity incompletely defines the genome-wide occupancy of Myc. Genome Biol. 15, 482 (2014).
Chacón Simon, S. et al. Discovery of WD repeat-containing protein 5 (WDR5)–MYC inhibitors using fragment-based methods and structure-based design. J. Med. Chem. 63, 4315–4333 (2020).
Han, H. et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell 36, 483–497.e15 (2019).
Tu, W. B. et al. Myc and its interactors take shape. Biochim. Biophys. Acta 1849, 469–483 (2015).
Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).
Cochran, A. G., Conery, A. R. & Sims, R. J. Bromodomains: a new target class for drug development. Nat. Rev. Drug Discov. 18, 609–628 (2019).
Lu, H. et al. Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal. Transduct. Target. Ther. 5, 213 (2020).
Cang, S., Iragavarapu, C., Savooji, J., Song, Y. & Liu, D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J. Hematol. Oncol. 8, 129 (2015).
Deeks, E. D. Venetoclax: first global approval. Drugs 76, 979–987 (2016).
Khurana, A. & Shafer, D. A. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco. Targets. Ther. 12, 2903–2910 (2019).
Dingar, D. et al. BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors. J. Proteom. 118, 95–111 (2015).
Macdonald, J. D. et al. Discovery and optimization of salicylic acid-derived sulfonamide inhibitors of the WD repeat-containing protein 5-MYC protein-protein interaction. J. Med. Chem. 62, 11232–11259 (2019).
Whitfield, J. R., Beaulieu, M.-E. & Soucek, L. Strategies to inhibit Myc and their clinical applicability. Front. Cell Dev. Biol. 5, 10 (2017).
Allen-Petersen, B. L. & Sears, R. C. Mission possible: advances in MYC therapeutic targeting in cancer. BioDrugs 33, 539–553 (2019).
Seo, H. K. et al. Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer. Oncotarget 5, 326–337 (2014).
Wang, H. et al. Improved low molecular weight Myc-Max inhibitors. Mol. Cancer Ther. 6, 2399–2408 (2007).
Stellas, D. et al. Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. JNCI J. Natl. Cancer Inst. 106, dju320 (2014).
Soucek, L. et al. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17, 2463–2472 (1998).
Jung, L. A. et al. OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors. Oncogene 36, 1911–1924 (2017).
Galardi, S. et al. Resetting cancer stem cell regulatory nodes upon MYC inhibition. EMBO Rep. 17, 1872–1889 (2016).
Soucek, L. et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 27, 504–513 (2013).
Soucek, L. et al. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 62, 3507–3510 (2002).
Soucek, L., Nasi, S. & Evan, G. I. Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ. 11, 1038–1045 (2004).
Annibali, D. et al. Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat. Commun. 5, 4632 (2014).
Beaulieu, M. E. et al. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy. Sci. Transl. Med. 11, 1–14 (2019).
Xu, J., Chen, G., De Jong, A. T., Shahravan, S. H. & Shin, J. A. Max-E47, a designed minimalist protein that targets the E-box DNA site in vivo and in vitro. J. Am. Chem. Soc. 131, 7839–7848 (2009).
Lustig, L. C. et al. Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth. Oncogene 36, 6830–6837 (2017).
Massó-Vallés, D. & Soucek, L. Blocking Myc to treat cancer: reflecting on two decades of Omomyc. Cells 9, 883 (2020).
Patel, M. C. et al. BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Mol. Cell. Biol. 33, 2497–2507 (2013).
Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
Singleton, K. R. et al. Melanoma therapeutic strategies that select against resistance by exploiting MYC-driven evolutionary convergence. Cell Rep. 21, 2796–2812 (2017).
Otto, C. et al. Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells. Neoplasia 21, 1110–1120 (2019).
Bandopadhayay, P. et al. Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma. Nat. Commun. 10, 2400 (2019).
Bagratuni, T. et al. JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer. Eur. J. Cancer 126, 125–135 (2020).
Alqahtani, A. et al. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Sci. 5, FSO372 (2019).
Andrieu, G., Belkina, A. C. & Denis, G. V. Clinical trials for BET inhibitors run ahead of the science. Drug Discov. Today Technol. 19, 45–50 (2016).
Feris, E. J., Hinds, J. W. & Cole, M. D. Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex. PLoS ONE 14, e0225784 (2019).
Huang, C. H. et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28, 1800–1814 (2014).
Chipumuro, E. et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159, 1126–1139 (2014).
Christensen, C. L. et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909–922 (2014).
Lu, P. et al. THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer. Oncogene 38, 3932–3945 (2019).
Hashiguchi, T. et al. Cyclin-dependent kinase-9 is a therapeutic target in MYC-expressing diffuse large B-cell lymphoma. Mol. Cancer Ther. 18, 1520–1532 (2019).
Wang, Y. et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 163, 174–186 (2015).
Blake, D. R. et al. Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer. Sci. Signal. 12, 549–562 (2019).
Jeong, K.-C., Ahn, K.-O. & Yang, C.-H. Small-molecule inhibitors of c-Myc transcriptional factor suppress proliferation and induce apoptosis of promyelocytic leukemia cell via cell cycle arrest. Mol. Biosyst. 6, 1503 (2010).
Guo, J. et al. Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice. Cancer Chemother. Pharmacol. 63, 615–625 (2009).
Lu, X., Vogt, P. K., Boger, D. L. & Lunec, J. Disruption of the MYC transcriptional function by a small-molecule antagonist of MYC/MAX dimerization. Oncol. Rep. 19, 825–830 (2008).
Yap, J. L. et al. Pharmacophore identification of c-Myc inhibitor 10074-G5. Bioorg. Med. Chem. Lett. 23, 370–374 (2013).
Castell, A. et al. A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation. Sci. Rep. 8, 10064 (2018).
Draeger, L. J. & Mullen, G. P. Interaction of the bHLH-zip domain of c-Myc with H1-type peptides. Characterization of helicity in the H1 peptides by NMR. J. Biol. Chem. 269, 1785–1793 (1994).
Ting, T. A., Chaumet, A. & Bard, F. A. Targeting c-Myc with a novel peptide nuclear delivery device. Sci. Rep. 10, 17762 (2020).
Soodgupta, D. et al. Small molecule MYC inhibitor conjugated to integrin-targeted nanoparticles extends survival in a mouse model of disseminated multiple myeloma. Mol. Cancer Ther. 14, 1286–1294 (2015).
Hart, J. R. et al. Inhibitor of MYC identified in a Krohnke pyridine library. Proc. Natl Acad. Sci. USA 111, 12556–12561 (2014).
Carabet, L. A. et al. Computer-aided drug discovery of Myc-max inhibitors as potential therapeutics for prostate cancer. Eur. J. Med. Chem. 160, 108–119 (2018).
Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional addiction in cancer. Cell 168, 629–643 (2017).
Jung, M. et al. A Myc activity signature predicts poor clinical outcomes in Myc-associated cancers. Cancer Res. 77, 971–981 (2017).
Li, Y., Casey, S. C. & Felsher, D. W. Inactivation of MYC reverses tumorigenesis. J. Intern. Med. 276, 52–60 (2014).
Acknowledgements
The authors thank all the members of the Penn laboratory for their feedback and helpful discussions, especially A. Tamachi, who was an important editor and contributor to the structure of the Perspective.
Author information
Authors and Affiliations
Contributions
C.L., D.R., C.R., P.L., A.S.M., R.C. and T.M.G.K. researched data for the article, substantially contributed to discussion of the content, wrote the article and reviewed or edited the article before submission. Y.W. researched data for the article, substantially contributed to discussion of the content and wrote the article. D.W.A., M.S., C.H.A. and B.R. reviewed or edited the article before submission. L.Z.P. researched data for the article, substantially contributed to discussion of the content and reviewed and edited the article before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Cancer thanks E. Prochownik, L. Soucek and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Lourenco, C., Resetca, D., Redel, C. et al. MYC protein interactors in gene transcription and cancer. Nat Rev Cancer 21, 579–591 (2021). https://doi.org/10.1038/s41568-021-00367-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41568-021-00367-9
This article is cited by
-
Asymmetric division of stem cells and its cancer relevance
Cell Regeneration (2024)
-
ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion
Cell Death Discovery (2024)
-
TRAIP suppresses bladder cancer progression by catalyzing K48-linked polyubiquitination of MYC
Oncogene (2024)
-
MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch
Nature Genetics (2024)
-
CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
Nature Communications (2024)
