Lysine methylation of promoter-bound transcription factors and relevance to cancer

Abstract

p53, NFκB, STAT3, and several other transcription factors are reversibly methylated on lysine residues by enzymes that also modify histones. The methylations of NFκB and STAT3 take place when they are bound to promoters, suggesting a more general model in which the binding of inducible transcription factors to DNA helps to recruit chromatin-modification machinery, which then may modify not only histones but also the bound transcription factors. Mutations of some histone-lysine methyltransferases and demethylases are linked to cancer, and these mutations may alter the methylation not only of histones but also of transcription factors, and thus may be tumorigenic through more than one mechanism. In recent years, much attention has been focused on posttranslational modification of chromatin because of its critical role in regulating gene expression [1]. The N-terminal tails of histones, as well as positions in the globular domains, carry methylations, acetylations, phosphorylations, ADP ribosylations, ubiquitinations, sumoylations, and other modifications [2]. Many different amino acid residues of each of the four core histones have been identified as modification sites [3] and some lysine side chains can be methylated or acetylated alternatively. These modifications provide entry sites for accessory proteins that help to determine higher order chromatin organization, leading to the activation or inactivation of specific genes. The lysine ε-amino groups can receive one, two, or three methyl groups and the extent of lysine methylation at a single lysine residue can be read differently by different effector proteins [4]. H3K4 methylation is associated with an early-elongating form of RNA polymerase II at actively transcribed genes, H3K9 and H3K27 methylation are linked to heterochromatin formation, while H3K36 methylation provides a stable molecular mechanism for establishing chromatin context throughout the genome by distinguishing potential regulatory regions from transcribed chromatin [5]. Moreover, increasing evidence indicates that nonhistone proteins are subject to reversible acetylation or methylation by histone-modifying enzymes. Among these nonhistone targets are transcription factors, hormone receptors, signal transducers, chaperones, and proteins of the cytoskeleton [6][7][8][9][10][11][12]. Although the acetylation of nonhistone proteins has been appreciated for some time [9,13,14], their methylation has been recognized only more recently. Here, we provide a summary of recent work showing lysine methylation of transcription factors that have well-recognized roles in tumorigenesis and of the effects of mutations of lysine methyltransferases and demethylases in cancer, and we cite evidence that at least some modifications take place only on promoter-bound transcription factors. Lysine methylation of nonhistone proteinsReversible modification of histones by methylation and demethylation, which occur at both lysine and arginine residues, plays an important role in many biological processes, including transcri...

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2

“…Lysine methylation by histone-modifying enzymes activates several different transcription factors, including STAT3, p53, and NF-κB, that have well-recognized roles in tumorigenesis. Therefore, mutations, amplifications, or deletions of histone lysine methyltransferases and demethylases that also modify transcription factors may affect cancer development and progression significantly (14). For this reason, these enzymes are promising targets for antitumor drugs.…”

“…Stark et al (14,15) show that gene-specific inducible modifications of transcription factors occur at promoters, where the local chromatin machinery is active, and that these modifications can modulate the local functions of the transcription factors by altering their stability, transactivation potency, and affinity for DNA, in turn affecting the strength and duration of inducible gene expression. Therefore we tested whether EZH2, the enzyme responsible for K49 dimethylation of STAT3, inhibits STAT3 binding to the SOCS3 promoter.…”

“…Ray et al (12) reported that IL-6-induced gene expression requires p300-mediated acetylation of K49 and K87 and that monoubiquitination at K97 is a key mediator of BRD4-dependent gene expression (13). Like NF-κB and p53, STAT3 is reversibly methylated on lysine residues by histone-modifying enzymes, with important functional consequences (14). Furthermore, STAT3 is known to be di-or trimethylated on K140 or K180 by the histone methyltransferase SET9 (SET domain containing lysine methyltransferase 9) or EZH2 (enhancer of zeste homolog 2), respectively (15,16).…”

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

“…The docking site for SET9 is provided by the phosphorylated S727 residue of STAT3, because the S727A mutant of STAT3 fails to recruit SET9 to the promoter. We reviewed several additional examples of the lysine methylation of promoter-bound transcription factors (Stark et al 2011). Our working hypothesis, which needs to be tested further, is that the promoter-bound factor provides a docking site for a histone-modifying enzyme that then catalyzes functionally important modifications, not only of the transcription factor but potentially also of local histones and the transcriptional machinery itself.…”

Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3

“…Recently, Ray et al (8) reported that STAT3 mono-ubiquitination at Lys-97 is a key mediator of BRD4-dependent antiapoptotic and pro-proliferative gene expression. Several transcription factors, including STAT3, NF-B, 2 and p53, are reversibly methylated on lysine residues by histonemodifying enzymes, with profound consequences for their functions (9). STAT3 is methylated on Lys-140 and Lys-180 by the histone methyl transferases SET9 and EZH2, respectively (10,11).…”