Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

Abstract

Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

Keywords: DNA methylation; HNSCC (Head and Neck Squamous Cell Carcinoma); acetylation; cancer stem cell; chemoresistance; epigenetics; histone H3; histone modifications; microRNA.

Figure 1

Changes in nuclear morphology may be associated with epigenetic modifications and deregulation of gene expression. (A) Immunocytochemistry of a head and neck squamous carcinoma (HNSCC) tumor sample stained for acetyl-H3 (Lys9). Note differences in the nuclear size and high levels of histone acetylation (red arrows, dark brown); (B) Immunofluorescence of an HNSCC tumor sample stained for acetyl-H3 (Lys9). Note differences in the nuclear size and protein accumulation depicted by yellow arrows. Scale bars represent 50 μm. Experimental procedure is described in [88].

Figure 2

Overview of epigenetic alterations involved in the HNSCC progression and resistance to therapy. (A) DNA hypermethylation of the tumor suppressor CDKN2A/p16^INK4a is the most frequent epigenetic modification observed in HNSCC, leading to cellular proliferation; (B) Changes in the chromatin structure lead to histone deacetylation and methylation of lysine in the histone tails resulting in gene silencing; (C) MicroRNAs work as a tumor suppressor and oncogenes regulate genes involved in HNSCC tumorigenesis. miR-22 acts as a tumor suppressor, controlling the levels of CD147 and it is frequently downregulated in HNSCC, increasing processes like proliferation, migration, and invasion (upper image). miR-21 is accumulated in HNSCC, showing oncogenic characteristics by targeting PDCD4 gene increasing resistance to cisplatin treatment (lower image).