Since the discovery of the MYC gene family in the early 1980s, it has rapidly become a focal point in cancer research. As proto-oncogenes within cells, the dysfunction of MYC is not only closely associated with the onset of various cancers but also plays a critical role in cancer progression. Initially, MYC was identified as the cellular homolog of the v-Myc oncogene from a retrovirus. Subsequent research revealed that MYC dysregulation is linked to various cancer types, including chromosomal translocations in Burkitt lymphoma, gene amplification in leukemia, chromosomal ring structure abnormalities, and cervical cancer caused by HPV insertion.

Structure and Function of MYC Genes

The MYC gene family consists of three homologous genes: MYC (c-MYC), MYCN (N-MYC), and MYCL (L-MYC). Although the proteins encoded by these genes share high structural and functional similarity, they are located on different chromosomes—MYCL on chromosome 1, MYCN on chromosome 2, and MYC on chromosome 8. These genes exhibit unique regulatory patterns, being expressed at different times and locations during cellular differentiation.

MYC proteins are composed of 439 amino acids and include an N-terminal transcriptional activation domain (TAD) and a C-terminal DNA-binding domain. The TAD forms an intrinsically disordered region essential for MYC's biological activity and transcriptional activation function. The C-terminal basic helix-loop-helix (bHLH) domain forms heterodimers with the MAX protein and binds specific DNA sequences (E-box), thereby regulating a broad array of gene expressions. The precise interactions of these domains are crucial for MYC's function within cells.

Figure 1. MYC acts as a transcriptional amplifier, boosting the expression of actively transcribed genes beyond normal levels in the presence of activators. (Jha RK, et al., 2023)

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Oncogenic Mechanisms of MYC Genes

Dysregulation of MYC genes is often closely associated with the development of cancer. Research indicates that overexpression of MYC proteins can bypass normal cell growth controls, leading to uncontrolled cell proliferation. MYC forms heterodimers with the MAX protein through its bHLH domain, binds to E-box sequences on DNA, and initiates gene transcription. MYC amplifies transcriptional output through complex interactions with transcription factors, co-activators, and chromatin-modifying proteins, driving excessive cell proliferation. However, it is noteworthy that MYC overexpression in non-transformed cells often induces apoptosis, suggesting that high levels of MYC expression are unsustainable in a normal cellular environment. This phenomenon further supports MYC's oncogenic role in cancer: when MYC undergoes mutations or amplification in cancer, its protein expression levels significantly increase, leading to uncontrolled cell growth and division, ultimately resulting in tumor formation and progression.

Physiological Functions of the MYC Gene Family

Beyond its role in cancer, the MYC gene is critical in normal physiological processes. In non-transformed cells, MYC is considered an immediate early gene, stably expressed during the G0 phase of the cell cycle but transiently upregulated during the transition to the G1/S phase. When cells enter a steady-state growth cycle, MYC is expressed at low levels until cell proliferation ceases again. Analysis of mRNA expression reveals that MYC not only upregulates many genes related to cell cycle progression but also downregulates a small subset of cell cycle antagonists. This indicates that the MYC gene not only promotes cell proliferation but also, under specific circumstances, suppresses excessive cell proliferation through complex regulatory mechanisms, ensuring precise control of cell growth.

Figure 2. MYC facilitates immune evasion in tumors through various mechanisms. (Krenz B, et al., 2024)

Transcriptional Amplification by MYC

One of the most remarkable features of the MYC gene is its role in transcriptional amplification. While transcriptional activation typically involves transcription factors binding to specific DNA sequences, recruiting the transcriptional machinery, co-activators, and chromatin modifiers to initiate gene transcription, transcriptional amplification refers to the global enhancement of expression of all active genes within a cell. As a transcriptional amplifier, MYC interacts with RNA polymerase II (RNAP II) to significantly boost transcription levels across a wide range of genes. Studies have shown that MYC can bind to promoters in nearly all open chromatin regions, not just limited to specific E-box sequences. This transcriptional amplification is more effective on highly transcribed genes, thereby raising the expression ceiling of these genes. This unique ability of MYC to globally regulate cell growth and proliferation explains its critical role in cancer development.

Interactions and Regulation of the MYC Gene Family

The function of the MYC family proteins largely depends on the precise interactions within its different regions. Multiple MYC boxes (MB) within the transcriptional activation domain of MYC interact with various proteins, finely regulating MYC's transcriptional activity. For example, MYC box 0 (MB0) interacts with the general transcription factor TFIIF, playing a role in the regulation of transcription initiation. MYC box I (MBI) regulates the proteasome-mediated degradation of MYC, thus modulating the stability of the MYC protein. MYC box II (MBII) interacts with transcriptional co-activators such as TRRAP, GCN5, and TIP48, recruiting chromatin remodeling complexes and histone acetyltransferases to enhance transcriptional efficiency.

At the C-terminal end of MYC, MYC box III (MBIII) interacts with chromatin-modifying protein WDR5, promoting the methylation of histone H3 lysine 4 (H3K4), which enhances MYC's interaction with active promoters and further facilitates gene transcription. Additionally, MYC box IV (MBIV) plays a crucial role in regulating MYC's transcriptional activity and apoptosis induction, controlling key decisions in cell fate. These complex interaction networks underscore the multifunctionality of MYC proteins in cell growth regulation and elucidate their oncogenic mechanisms in cancer.

As a key regulator of cell proliferation and cancer development, the MYC gene family holds significant importance in cancer research. Through in-depth studies of MYC's structure and function, scientists have unveiled the oncogenic mechanisms of MYC in cancer and its regulatory roles in normal physiology. In the future, further exploration of the interaction networks and regulatory mechanisms of the MYC gene family may contribute to the development of targeted therapies for diseases associated with MYC dysregulation.