EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex

Lee, Ji Min; Lee, Jason S.; Kim, Hyun-Kyung; Kim, Kyeongkyu; Park, Hyejin; Kim, Ji Young; Lee, Jun Young; Kim, Ik Soo; Kim, Joomyung; Lee, Minkyoung; Chung, Chin Ha; Seo, Sang-Beom; Yoon, Jong Bok; Ko, Eunyoung; Noh, Dong‐Young; Kim, Keun Il; Kim, Kyeong Kyu; Baek, Sung Hee

doi:10.1016/j.molcel.2012.09.004

Cited by 205 publications

(190 citation statements)

References 39 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…Ezh2-null keratinocytes differentiate prematurely and express higher levels of EDC genes due to increased AP-1 transcription factor activity (Ezhkova et al 2009). It has been shown previously that Ezh2 can modify the activity of some transcription factors through methylation (He et al 2012a;Lee et al 2012;Xu et al 2012;Kim et al 2013). Employing MS-based approaches, we identified monomethylation and dimethylation on K104 of Fra-2 in basal keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Besides modifying histones, Ezh2 methylates nonhistone substrates, such as some transcription factors, thereby regulating their transcriptional activity (He et al 2012a;Lee et al 2012;Xu et al 2012;Kim et al 2013). Therefore, we investigated a potential histone methylation-independent role of Ezh2 on Fra-2 during epidermal differentiation employing coimmunoprecipitations (co-IPs).…”

Section: Fra-2 and Ezh2 Coregulate Epidermal Differentiation Genes Anmentioning

confidence: 99%

See 1 more Smart Citation

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

et al. 2014

View full text Add to dashboard Cite

Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Fra-2 and Ezh2 Coregulate Epidermal Differentiation Genes Anmentioning

confidence: 99%

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

et al. 2014

View full text Add to dashboard Cite

show abstract

“…RORα, an orphan nuclear receptor that is involved in several signaling pathways and that inhibits cancer progression in a context-dependent manner, is monomethylated by EZH2 and thus is marked for ubiquitin-mediated degradation (29). EZH2 has been reported to methylate the transcription factor GATA4, thereby repressing its activity (30).…”

Section: Discussionmentioning

confidence: 99%

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

Dasgupta¹,

Dermawan²,

Willard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

114

View full text Add to dashboard Cite

Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers. Connecting EZH2 to a functionally important methylation of STAT3, which is constitutively activated in many tumors, may help reveal the basis of the opposing roles of EZH2 in liquid and solid tumors and also may identify novel therapeutic opportunities.posttranslational modification | histone methyltransferase | gene expression S TAT3 is activated in 70% of all solid and hematological tumors (1, 2), where it stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. Recently, STAT3 also was found to have an important role in maintaining cancer stem cells, both in vitro and in mouse tumor models, indicating that it is integrally involved in tumor initiation, progression, and maintenance (3). IL-6-induced constitutive activation of STAT3 was observed in neoplastic gastric tissue and is positively correlated with tumor progression (4), and the expression of tyrosine-phosphorylated STAT3 is associated with poor prognosis in colorectal cancer, independent of the mutation status of MSI, CIMP, BRAF, or KRAS (5). The STAT3 gene is rarely mutated in cancer but rather is activated by members of the IL-6 family of cytokines, receptor tyrosine kinases, mutated JAKs, or oncogenic cellular tyrosine kinases, such as SRC (6). Because STAT3 is constitutively activated during disease progression and metastasis, it is a promising therapeutic target. Even though transcription factors are difficult drug targets, accumulating evidence for the crucial roles of posttranslational modifications of transcription factors in mediating target gene expression provides an opportunity to develop drugs against the modifying enzymes rather than against the transcription factors themselves.STAT3 is activated primarily by phosphorylation of Y705 (7) and secondarily by phosphorylation of S727 (8). The acetylation of STAT3 at K685 (9, 10) has been shown recently to have little or no effect on IL-6-dependent gene expression (11). 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). Here we show that IL-6-dependent, previously unident...

show abstract

“…However, these requirements are dependent on substrate receptors within specific Cullin-RING ligase complexes. Although the necessity of posttranslational modifications have not been well documented for Cul4-DDB1 substrates, methylation of orphan nuclear receptor ROR␣ by enhancer of zeste homolog 2 (EZH2) methyltransferase has been shown to facilitate its recognition by VPRBP (or DCAF1) of the Cul4-DDB1-DCAF1 ubiquitin ligase for subsequent ubiquitylation and degradation (86). Therefore, Ser-48 phosphorylation may potentially interfere with methylation-mediated ubiquitylation.…”

Section: Discussionmentioning

confidence: 99%

Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Pygo2 is a chromatin effector of the Wnt signaling pathway that regulates cell growth and differentiation. Results: Pygo2 is degraded through the ubiquitin/proteasome pathway and is stabilized by Akt phosphorylation at its serine 48. Conclusion: Stabilizing phosphorylation by Akt regulates Pygo2 protein expression. Significance: Pygo2 is a common nodule downstream of Wnt and Akt pathways.

show abstract

EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex

Cited by 205 publications

References 39 publications

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

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

Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation

Contact Info

Product

Resources

About