Several studies investigate the function and use of MYC, a multifunctional oncogene. Encoded by the Myc gene, this transcription factor is involved in ribosome biogenesis, cell-cycle progression and metabolism, protein translation, orchestrating a broad range of biological functions, such as cell proliferation, differentiation, survival, and immune surveillance (Fig. 1) (Dang et al., 2006, Meyer and Penn, 2008). Although strictly regulated in healthy non-proliferating cells, this super-transcription factor is overexpressed and deregulated in cancer (Ahmadi, Rahimi, Zarandi, Chegeni, & Safa, 2021). MYC expression is deregulated in 70% of human malignancies by events like chromosomal translocation, enhancer activation, and altered protein stability. In malignant cells, elevated levels of MYC expression promote tumorigenesis and metastasis, and one of the primary mechanisms is the reprogramming of metabolic pathways and bioenergetics. Tumor suppressor genes such as p53, metabolic pathways like the mTORC pathway, and transcription regulators like the FoxO transcription factor family all serve as metabolic regulators for the transcription and translation of the Myc oncogene. Furthermore, MYC regulates practically all glycolysis and glutaminolysis genes, thus affecting the expression of numerous downstream targets, and several reports indicate that inhibition of glycolysis and glutaminolysis enzymes stall cell proliferation (Stine, Walton, Altman, Hsieh, & Dang, 2015). In addition, MYC is also closely linked to amino acid metabolism, nucleotide metabolism, and lipid metabolism. While the crosstalk between MYC activation and lipid metabolism has not been studied as widely as that of glucose metabolism, it is now well-established that MYC activates all three enzymes (ACC, FASN, and HMGCR) necessary for lipid metabolism, thus highlighting the importance of lipid metabolism pathways in the MYC pathway. Additionally, multiple drugs are currently undergoing clinical trials to understand whether targeting these enzymes may contribute to reductions in MYC-driven cancers (Dong, Tu, Liu, & Qing, 2020).

The Myc gene family embraces three members: C- Myc, L- Myc, and N- Myc, all belonging to the superfamily of basic helix-loop-helix leucine zipper DNA binding proteins (Beaulieu et al., 2020, Carroll et al., 2018, Dang, 2016). Each member owns three primary domains. The N-terminal region possesses the transactivation domain, the central region is comprised of nuclear localization and stability control, and the C-terminal region is tangled with its obligatory partner, MAX, as well as binding to DNA (Conacci-Sorrell, McFerrin, & Eisenman, 2014). Dimerization with MAX exhibits a central role in enabling Myc to modulate gene transcription (Dang, 2016). As mentioned earlier, in healthy adult tissues, the expression of MYC is rigorously regulated. However, in various human cancers, Myc experiences structural alterations or overexpression. These cellular alterations have been identified in approximately 70% of human malignancies (Beaulieu et al., 2020, Dang, 2016). Mechanisms paramount to these alterations comprise gene amplification, retroviral promoter insertion, chromosomal translocation, enhanced cell signaling, activation of super-enhancers, altered protein degradation, and mutation (Table 1) (Adams et al., 1985, Kalkat et al., 2017, Principles of systems biology. No. 25 Cell System 6 1 2018 2 4 doi: 10.1016/j.cels.2018.01.006.PMID: 29401449, Schick et al., 2017, Xu-Monette et al., 2016, Tarrado-Castellarnau et al., 2016).

One of the more recurrent mechanisms for activating Myc in solid human cancers seems to be gene amplification among various mechanisms. Recent investigations conducted by The Cancer Genome Atlas (TCGA) network, utilizing approximately 9000 samples across 33 tumor types, revealed that 28% of human cancers exhibit amplification in at least one of the MYC genes (Principles of Systems Biology, 2018). The most frequent occurrences of c-Myc amplification are reported in ovarian cancer (64%), esophageal cancer (45.3%), squamous lung cancer (37.2%), and breast cancer (30%) (Principles of Systems Biology, 2018). However, the occurrence of Myc amplification within a specific cancer type may vary based on its molecular subtype. For instance, in the basal/triple-negative breast cancer (TNBC), perceived as the most challenging to treat, C-Myc is amplified in 34%–44% of samples, as opposed to only 7%–13% in luminal A-type (ER/PR-positive) cancers, which have a more favorable outcome (AlSultan et al., 2021).

Elevated Myc mRNA and protein expression and/or stability can occur due to an increase in signaling through the ERK, PI3K, or β-catenin signaling pathways in cancers lacking Myc genetic alterations such as amplification or translocation (Hayes et al., 2016, Liu et al., 2011, Yochum et al., 2010). Beyond these signaling mechanisms, recent data revealed that the loss of the p53 function can also activate c-Myc (Santoro et al., 2019). Finally, various post-translational modifications (phosphorylation, acetylation, sumoylation) and E3 ubiquitin ligase recruitment (via FBW7 or SKP2) can modulate Myc protein stability, leading to proteasomal degradation (Kalkat et al., 2017, Yumimoto and Nakayama, 2020).

The mRNA of c-Myc shows a brief lifespan, and in the lack of positive regulatory signals, the transcription of c-Myc decreases, leading to low levels of c-Myc protein and no proliferative stimulation. Contrariwise, in tumor cells, the function of c-Myc is frequently enhanced, often due to mutations in the gene itself or more commonly through the induction of c-Myc expression via upstream oncogenic pathways. Regardless of its oncogenic properties, c-Myc has a neutralizing ability to stimulate apoptosis through different pathways (Kelly and Rickinson, 2007, Pelengaris et al., 2002). This contradiction likely accounts for the exceptional role of c-Myc as the primary oncogene in early detected tumors. Another protective shield firmly regulating c-Myc expression is the stability of the c-Myc protein. The short half-life of c-Myc in proliferating cells, approximately 30 min (Hann & Eisenman, 1984), exhibits a highly effective mechanism of gene regulation. Increasing evidence has revealed the ubiquitylation and degradation of c-Myc by the proteasome (Ciechanover et al., 1991, Salghetti et al., 1999), including phosphorylation-dependent degradation (Yada et al., 2004). Contrariwise, c-Myc hyperregulation may result from post-translational modifications. Notably, mutations in the coding region of c-Myc, especially in the Thr58 phosphorylation site, are repeatedly reported in human lymphomas. This mutation elevates the transforming activity of c-Myc by causing incompetent ubiquitination and lessened proteasome-mediated protein turnover (Bahram, von der Lehr, Cetinkaya, & Larsson, 2000).

MicroRNAs (miRNAs) play a prime role in the c-Myc regulatory network, functioning both as targets of c-Myc and as regulators of c-Myc expression. The application of microarray technology has unwrapped miRNAs that are both induced and repressed by c-Myc. One inevitably repressed miRNA by c-Myc across multiple tumors is miR-26a (Sander, Bullinger, & Wirth, 2009). On the contrary, overexpression of let-7a miRNA results in notable downregulation in c-Myc gene expression and its target genes, along with antiproliferative activity in lymphoma cells (Sampson et al., 2007). Moreover, recent studies have revealed that miR-33b22, miR-143, and miR-145 actively suppress ERK5/c-Myc signaling (Takaoka et al., 2012).