Tumor-suppressive functions of protein lysine methyltransferases

Abstract

Protein lysine methyltransferases (PKMTs) play crucial roles in histone and nonhistone modifications, and their dysregulation has been linked to the development and progression of cancer. While the majority of studies have focused on the oncogenic functions of PKMTs, extensive evidence has indicated that these enzymes also play roles in tumor suppression by regulating the stability of p53 and β-catenin, promoting α-tubulin-mediated genomic stability, and regulating the transcription of oncogenes and tumor suppressors. Despite their contradictory roles in tumorigenesis, many PKMTs have been identified as potential therapeutic targets for cancer treatment. However, PKMT inhibitors may have unintended negative effects depending on the specific cancer type and target enzyme. Therefore, this review aims to comprehensively summarize the tumor-suppressive effects of PKMTs and to provide new insights into the development of anticancer drugs targeting PKMTs.

Fig. 1. Characteristics of protein lysine methylation.

a The process of protein lysine methylation. b Molecular functions of protein lysine methylation.

Fig. 2. Domain structure of tumor-suppressive protein lysine methyltransferases.

This illustration portrays the configuration of domains within lysine methyltransferase proteins, acknowledged for its role in suppressing tumors. Each domain is assigned a distinct color to indicate commonalities or differences among various methyltransferases. The universal presence of the red SET domain in all tumor-suppressive lysine methyltransferases, excluding DOT1L, underscores the pivotal role of their catalytic activity in tumor suppression. Fyr-C Phe/Tyr-rich domain C-terminal, Fyr-N Phe/Tyr-rich domain N-terminal, SET Su(var)3-9 Enhancer-of-zeste Trithorax-domain, DHHC Asp-His-His-Cys containing domain, AWS associated with SET domains, MORN membrane occupation and recognition nexus, PWWP Pro-Trp-Trp-Pro containing domain, CXC Cys-rich domain, DOT1L catalytic domain of DOT1L, WW domain with 2 conserved Trp-Trp residues, MBD methyl-CpG binding domain, Tudor tudor domain, Chormo Chromatin organization modifier domain.

Fig. 3. The context-dependent tumor-suppressive effect of methyltransferases.

a Various tumor types controlled by three lysine methyltransferase variants that are frequently linked to tumor suppressor functions. b Mechanistic role of SETD2 as a tumor suppressor in clear-cell renal cell carcinoma. Reduction in SETD2 levels results in a decrease in H3K36 trimethylation and tubulin α-1a trimethylation, which subsequently initiates genomic instability. c The mechanism of action of SETD7 as a tumor suppressor. Left: SETD7 catalyzes the monomethylation of β-catenin at K180, amplifying its molecular interaction with GSK3β. This prompts GSK3β-mediated phosphorylation, leading to ubiquitination of β-catenin followed by proteasomal degradation in HeLa cells. Consequently, this process leads to diminished levels of c-Myc and cyclin D1, resulting in a decrease in cell proliferation. Right: In an in vivo model, SETD7 initiates monomethylation of p53 at K372, leading to its interaction with Tip1. This interaction subsequently induces acetylation of p53, resulting in the activation of p53 itself. This activation leads to heightened levels of p21 and the preservation of the DNA damage response. d Upper: Structure of EZH2 with domain WDB, WD-40 binding domain; D1, domain 1; D2, domain 2; CXC, Cys-rich domain; SET, catalytic domain of EZH2. Lower: The mechanistic role of EZH2 as a tumor suppressor in lung adenocarcinoma, myelodysplastic disorders, and T-cell acute lymphoblastic leukemia (T-ALL) through its involvement in modulating the trimethylation status of H3K27. Decreased expression and mutation of EZH2 (as depicted) have been identified in individuals with lung adenocarcinoma, myelodysplastic syndromes, and T-ALL. The attenuation of EZH2 expression or activity leads to a reduction in H3K27me3 levels, resulting in enhanced activation of downstream proteins such as AKT, ERK, Nrf2, Myc, and NOTCH1, which are implicated in the development of these conditions.

Fig. 4. Gene expression analysis and clinical relevance of SETD2, SETD7, and EZH2.

a, d, g A general pancancer overview of copy number variations (CNVs) in SETD2, SETD7, and EZH2, including copy number gain and copy number loss. The X-axis represents cancer type, while the Y-axis displays the frequencies of alterations (including both amplification and deletion) as percentages. The colors blue and red indicate deletion and amplification, respectively. b, e, h RNA expression profiles of SETD2, SETD7, and EZH2 based on RNA-seq data from The Cancer Genome Atlas. c, f, i Kaplan‒Meier analysis of recurrence-free survival (RFS) or overall survival (OS) based on the expression levels of SETD2, SETD7, and EZH2 in breast, gastric, lung, and ovarian cancers. ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC lymphoid neoplasm diffuse large B-cell lymphoma, ESCA esophageal carcinoma, HNSC head and neck squamous cell carcinoma, KICH kidney chromophobe, KIRC kidney renal clear cell carcinoma, LAML acute myeloid leukemia, LGG lower-grade glioma, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectal adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumor, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma.

Fig. 4. Gene expression analysis and clinical relevance of SETD2, SETD7, and EZH2.

a, d, g A general pancancer overview of copy number variations (CNVs) in SETD2, SETD7, and EZH2, including copy number gain and copy number loss. The X-axis represents cancer type, while the Y-axis displays the frequencies of alterations (including both amplification and deletion) as percentages. The colors blue and red indicate deletion and amplification, respectively. b, e, h RNA expression profiles of SETD2, SETD7, and EZH2 based on RNA-seq data from The Cancer Genome Atlas. c, f, i Kaplan‒Meier analysis of recurrence-free survival (RFS) or overall survival (OS) based on the expression levels of SETD2, SETD7, and EZH2 in breast, gastric, lung, and ovarian cancers. ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC lymphoid neoplasm diffuse large B-cell lymphoma, ESCA esophageal carcinoma, HNSC head and neck squamous cell carcinoma, KICH kidney chromophobe, KIRC kidney renal clear cell carcinoma, LAML acute myeloid leukemia, LGG lower-grade glioma, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectal adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumor, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma.

Fig. 4. Gene expression analysis and clinical relevance of SETD2, SETD7, and EZH2.

a, d, g A general pancancer overview of copy number variations (CNVs) in SETD2, SETD7, and EZH2, including copy number gain and copy number loss. The X-axis represents cancer type, while the Y-axis displays the frequencies of alterations (including both amplification and deletion) as percentages. The colors blue and red indicate deletion and amplification, respectively. b, e, h RNA expression profiles of SETD2, SETD7, and EZH2 based on RNA-seq data from The Cancer Genome Atlas. c, f, i Kaplan‒Meier analysis of recurrence-free survival (RFS) or overall survival (OS) based on the expression levels of SETD2, SETD7, and EZH2 in breast, gastric, lung, and ovarian cancers. ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC lymphoid neoplasm diffuse large B-cell lymphoma, ESCA esophageal carcinoma, HNSC head and neck squamous cell carcinoma, KICH kidney chromophobe, KIRC kidney renal clear cell carcinoma, LAML acute myeloid leukemia, LGG lower-grade glioma, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectal adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumor, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma.