Transcription factors are a group of proteins that can bind to specific sequences upstream of the 5′ terminus of target genes, typically considered the promoter region1,2. In this way these transcription factors can inhibit or enhance gene expression and ensure specific temporal target gene expression3. Under normal circumstances, promoter-specific transcription factors contribute in basic biological activities including differentiation4, development5, and metabolism6. Importantly, dysregulation of these transcriptional programs can lead to malignant growth and cancer formation7,8. Transcription factors can be subject to a variety of enzyme-catalyzed post-translational modifications (PTMs) in response to environmental changes, especially in disease occurrence and tumorigenesis9,10.

These transcription factor PTMs are added and removed by the same enzyme families that are involved in histone modifications like acetylation, phosphorylation, and methylation11,12,13. Specific modifications have selective effects on transcription factor functions, resulting in specific gene expression alterations. It has been demonstrated in the literature that transcription factor phosphorylation and acetylation can promote carcinogenesis by regulating transcriptional activity14,15. We have greatly improved our understanding of transcription factor methylation with the development of mass-spectrometric techniques in the last few decades16.

Protein methylation occurs at specific sites on substrates, with lysine methylation being one of the important forms17,18,19. The lysine (K) ε-amino group of protein substrates can accept up to three methyl groups, resulting in either mono-, di-, or trimethyl lysine, in a process termed lysine methylation20,21,22. Recent studies have revealed that a number of transcription factors have been found to be modified by lysine methyltransferases (KMTs)23,24,25, resulting in specific gene expression alterations26,27. The abnormal expression of methyltransferases in many tumor types, which has been proven to be associated with tumorigenesis and cancer development, has become the focus of anticancer research28,29,30. In addition to histone methylation31, transcription factor methylation modification is also an important aspect for the development of cancer27,32.

To date, multiple studies have demonstrated that lysine methylation of transcription factors can directly regulate target gene expression by altering transcription factor stability and function. In this review, we summarize recent studies on lysine methylation of transcription factors, aiming to underline the biological significance and highlight the potential clinical value of lysine methylation of transcription factors in cancer.