The role of protein methyltransferases as potential novel therapeutic targets in squamous cell carcinoma of the head and neck

Abstract

Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates. This review summarizes the current knowledge on the function of protein methyltransferases in squamous cell carcinoma of the head and neck and highlights their promising potential as the next generation of therapeutic targets in this disease.

Keywords: EHMT2; EZH2; NSD1; NSD2; NSD3; PRMT1; PRMT5; Protein methylation; Protein methyltransferase; Squamous cell carcinoma of the head and neck.

Fig. 1.

Protein structure and mechanisms of action of the NSD family of protein methyltransferases in SCCHN. A. (i) Protein structure of NSD1 (UniProt, 2696 aminoacids). PWWP: domain with conserved proline-tryptophan-tryptophan-proline motif, PHD: plant homeodomain zinc finger, RING: really interesting new gene finger domain, AWS: associated with SET domain, SET: Su(var)3–9, Enhancer-of-zeste, Trithorax domain, PostSET: cysteine-rich motif following the SET domain, (ii) Mechanisms of action of NSD 1. Truncating NSD1 mutations downregulate chemokine expression in SCCHN cells, inducing T-cell exclusion from the tissue microenvironment. NSD1 mutations are also associated with decreased expression of epidermal differentiation genes in SCCHN. B. (i) Molecular structure of the long isoform of NSD2 (UniProt, 1365 aminoacids). Domains described as per A(i) and HMG: High mobility group domain, (ii) Mechanism of action of NSD2 in SCCHN. NSD2 di-methylates H3K36 and induces transcriptional upregulation of NIMA-related kinase 7 (NEK7), leading to entry of SCCHN cells to cytokinesis. C. (i) Molecular structure of the long isoform of NSD3 (UniProt, 1437 aminoacids). Domains described as per A(i). (ii) Mechanisms of action of NSD3. NSD3 di-methylates H3K36 and induces transcriptional upregulation of cell-cycle related genes CDC6 and CDK2, leading to promotion of Gl-S phase progression in SCCHN cells. Additionally, NSD3 directly mono-methylates the epidermal growth factor receptor (EGFR) at lysine K721 within its tyrosine kinase domain. This induces EGF-independent activation of EGFR and its downstream ERK pathway, as well as increased affinity of nuclear EGFR for PCNA and subsequent enhancement of DNA replication in SCCHN cells.

Fig. 2.

Molecular structure and mechanisms of action of EHMT2 in SCCHN. A. Molecular structure of EHMT2 (UniProt, 1210 aminoacids). ANK: ankyrin repeats, PreSET: N-terminal to SET, cys-rich putative Zn2+-binding domain, SET: Su(var)3–9, Enhancer-of-zeste, Trithorax, PostSET: cysteine-rich motif following the SET domain. B. Mechanisms of action of EHMT2. EHMT2 associates with Snail and induces silencing of E-cadherin through H3K9 mono- and di-methylation, leading to induction of epithelial-mesenchymal transition (EMT) and cancer sternness features in SCCHN cells. Additionally, EHMT2 binds to ATF4 to induce mono-methylation of H3K9 and transcriptional upregulation of the glutamate-cysteine ligase catalytic subunit which promotes cisplatin resistance.

Fig. 3.

Molecular structure and mechanisms of action of EZH2 in SCCHN. A. Molecular structure of EZH2 (UniProt, 751 aminoacids, isoform a). SANT: SANT SWI3, ADA2, N-CoR and TFIIIB” DNA-binding domain, CXC: Tesmin/TSOl-like CXC domain, SET: Su (var)3–9, Enhancer-of-zeste, Trithorax. B. Mechanisms of action of EZH2. EZH2 forms a repressive complex with histone deacetylase 1 (HDAC1), histone deacetylase 2 (HDAC2) and Snail and induces transcriptional silencing of E-cadherin through tri-methylation of H3K27 and EMT features in nasopharyngeal carcinoma cells. EZH2-in-duced tri-methylation of H3K27 also silences the expression of differentiation genes in SCCHN.

Fig. 4.

Protein structure and mechanisms of action of PRMT1 in SCCHN. A. Protein structure of PRMT1 (UniProt, 361 aminoacids, isoform 1). Signature motif I, post I, post II, post III, conserved TWH loop: tandem winged-helix. B. Mechanisms of action of PRMT1. PRMT1 and lymphotoxin-β (LTβ) are upregulated by Snail in SCCHN cells with EMT features. PRMT1 then methylates EGFR at R198/R200, and LTβ preferentially interacts with R198/R200-methylated EGFR, inducing its activation and resistance to Cetuximab.