Epigenetic Regulation in Oral Squamous Cell Carcinoma Microenvironment: A Comprehensive Review

Abstract

Oral squamous cell carcinoma (OSCC) is a prevalent and significant type of oral cancer that has far-reaching health implications worldwide. Epigenetics, a field focused on studying heritable changes in gene expression without modifying DNA sequence, plays a pivotal role in OSCC. Epigenetic changes, encompassing DNA methylation, histone modifications, and miRNAs, exert control over gene activity and cellular characteristics. In OSCC, aberrant DNA methylation of tumor suppressor genes (TSG) leads to their inactivation, subsequently facilitating tumor growth. As a result, distinct patterns of gene methylation hold promise as valuable biomarkers for the detection of OSCC. Oral cancer treatment typically involves surgery, radiation therapy, and chemotherapy, but even with these treatments, cancer cells cannot be effectively targeted and destroyed. Researchers are therefore exploring new methods to target and eliminate cancer cells. One promising approach is the use of epigenetic modifiers, such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, which have been shown to modify abnormal epigenetic patterns in OSCC cells, leading to the reactivation of TSGs and the suppression of oncogenes. As a result, epigenetic-targeted therapies have the potential to directly alter gene expression and minimize side effects. Several studies have explored the efficacy of such therapies in the treatment of OSCC. Although studies have investigated the efficacy of epigenetic therapies, challenges in identifying reliable biomarkers and developing effective combination treatments are acknowledged. Of note, epigenetic mechanisms play a significant role in drug resistance in OSCC and other cancers. Aberrant DNA methylation can silence tumor suppressor genes, while alterations in histone modifications and chromatin remodeling affect gene expression related to drug metabolism and cell survival. Thus, understanding and targeting these epigenetic processes offer potential strategies to overcome drug resistance and improve the efficacy of cancer treatments in OSCC. This comprehensive review focuses on the complex interplay between epigenetic alterations and OSCC cells. This will involve a deep dive into the mechanisms underlying epigenetic modifications and their impact on OSCC, including its initiation, progression, and metastasis. Furthermore, this review will present the role of epigenetics in the treatment and diagnosis of OSCC.

Keywords: DNA methylation; drug resistance; epigenetic; oral squamous cell carcinoma; tumor microenvironment.

Figure 1

The TME refers to the complex cellular and non-cellular components surrounding a tumor, which interact and influence tumor growth, progression, and response to treatment. It consists of various cell types, including tumor cells, immune cells, fibroblasts, endothelial cells, and adipocytes, as well as extracellular matrix components, cytokines, growth factors, and signaling molecules. The TME plays a critical role in shaping tumor behavior by promoting angiogenesis, facilitating immune evasion, inducing tissue remodeling, and providing a supportive niche for tumor cells [78].

Figure 2

DNA methylation is a crucial biochemical process that adds or removes a methyl group from the DNA molecule and plays a crucial role in gene regulation, genomic stability, and cellular differentiation. It involves two main processes: de novo methylation, which establishes new DNA methylation patterns during early development or in specific cell types, and demethylation, which removes methyl groups from the DNA molecule. De novo methylation is essential for embryonic development, tissue-specific gene expression, and silencing of repetitive DNA elements. Demethylation can occur through active or passive demethylation, with active demethylation involving enzymatic processes such as oxidation and base excision (one prominent pathway involves the Ten-Eleven Translocation (TET) family of enzymes), while passive demethylation occurs through DNA replication without de novo methylation. Both processes play essential roles in the regulation of gene expression and cellular differentiation [87].

Figure 3

Aberrant DNA methylation is a key contributor to tumorigenesis and tumor formation and growth. Hypermethylation of tumor suppressor gene promoters leads to their silencing, impairing their ability to regulate cell growth and prevent tumor formation. Conversely, hypomethylation of oncogene promoters activates these genes, promoting abnormal cell growth and tumor development. Genome-wide DNA hypomethylation, which reduces the methylation levels throughout the genome, can have dual effects. It may induce chromosomal instability, increase the likelihood of genetic mutations, and promote tumorigenesis. Hypomethylation can also drive cell differentiation and inhibit tumorigenesis by promoting normal cell development and function. These aberrant DNA methylation patterns play crucial roles in the complex mechanisms underlying cancer development.

Figure 4

The schematic diagram illustrates how IL-8, IL-6, and TNF-α are activated by macrophages in the tumor microenvironment. Upon activation, they initiate signaling pathways that affect various aspects of the tumor microenvironment, including inflammation, cell proliferation, and angiogenesis, which lead to cancer progression.

Figure 5

The PTEN tumor suppressor network is a vital part of the PI3K-Akt pathway, which regulates cell growth and survival. PTEN inhibits the pathway by reducing the levels of a signaling molecule called PIP3. When PTEN is inactive or lost in cancer, the PI3K-Akt pathway becomes overactive. This leads to increased activity of mTOR, a protein that controls cell growth and metabolism. Dysregulation of mTOR contributes to tumor progression and resistance to cancer therapies. Understanding this network is important for developing targeted treatments to restore pathway balance and inhibit cancer growth. Furthermore, dysregulated RAS-ERK pathways, triggered by mutations in RAS genes, promote uncontrolled cell growth. Growth factors in tumor microenvironments further stimulate this pathway, making targeting it a major focus in cancer research for therapeutic strategies [323,324,328].