Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis

Zeng, Yi; Qiu, Rongfang; Yang, Yang; Gao, Tianshu; Zheng, Yu; Huang, Wei; Gao, Jie; Zhang, Kai; Liu, Ruiqiong; Wang, Shuang; Hou, Yongzhong; Yu, Wenqian; Leng, Shuai; Feng, Dandan; Liu, Wei; Zhang, Xi; Wang, Yan

doi:10.1016/j.celrep.2019.10.004

Cited by 54 publications

(54 citation statements)

References 48 publications

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“…EZH2 , a histone H3 methyltransferase capable of catalyzing trimethylation on lysine 27 of histone H3 ( H3K27me3 ), mediates the metastasis of various types of tumors ( 39 , 43 – 45 ). In addition, the TGFB signaling pathway plays a crucial role in tumor metastasis ( 11 , 36 , 46 ).…”

Section: Resultsmentioning

confidence: 99%

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EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis

Huang¹,

Hu²,

Song³

et al. 2022

Journal of Clinical Investigation

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SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 undergoes methylation at K53 and K333 by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation.Mechanistically, EZH2-triggered SMAD3 methylation facilitates SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustains SMAD3 phosphorylation by the TGFB receptor. Pathologically, EZH2 expression increasing results in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation is upregulated and correlated with SMAD3 hyperactivation in breast cancer, promotes tumor metastasis, and is predictive of poor survival outcome. We used two TAT-peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers in regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.

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Section: Resultsmentioning

confidence: 99%

“…EZH2, a histone H3 methyltransferase capable of catalyzing tri-methylation on the lysine 27 of histone H3 (H3K27me3), mediated various tumor metastasis (39,(43)(44)(45).…”

Section: Ezh2-mediated Tumor Metastasis Depended On Smad3 Methylationmentioning

confidence: 99%

EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis

Huang¹,

Hu²,

Song³

et al. 2022

Journal of Clinical Investigation

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“…Mechanistically, inhibition of SMYD2 suppressed the progression of renal cell carcinoma by downregulating microRNA-125b [ 16 ]. More relevantly, SMYD2 has been established to coordinate with EZH2 to promote breast cancer tumorigenesis and metastasis [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer

et al. 2021

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Background Colorectal cancer (CC) is one of the major contributors to tumor-related death worldwide, and its main cause of death is distant metastasis. Dysregulation of long non-coding RNA (lncRNA) LINC01605 has been implicated in CC. However, its role in metastasis of CC remains elusive. The goal of the study is to uncover the biological function and molecular mechanism of LINC01605 in CC. Methods The differentially expressed lncRNAs were first screened from GSE97300, GSE84983, GSE110715, GSE70880, and GSE75970 microarrays. The correlation between the expression of LINC01605 and the clinical phenotypes of enrolled CC patients (n = 134) was subsequently analyzed. The upstream and downstream regulatory mechanisms of LINC01605 in CC were identified through bioinformatics and RNA-seq analyses. Finally, the effects of related factors on CC cell growth and metastasis were confirmed through functional validation experiments. Results LINC01605, significantly highly expressed in CC, was a prognostic factor for patients with CC. Functional experiments revealed that LINC01605 knockdown inhibited the proliferatory and metastatic potential of CC cells in vitro and in vivo. Moreover, LINC01605 was regulated by SMYD2-EP300-mediated modifications of histone H3K4me3 as well as H3K27ac. LINC01605 was found to bind to METTL3 and promote the m6A modification of SPTBN2 mRNA, thereby facilitating the translation of SPTBN2. Conclusions Overexpression of LINC01605, regulated by SMYD2-EP300-mediated H3K27ac and H3K4me3 modifications, bound to METTL3 protein to promote m6A modification of SPTBN2 mRNA, leading to the development of CC.

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“…The MEK–ERK pathway ( 142 ) and lncRNA ANCR ( 143 ) can regulate EZH2 levels to impact breast cancer metastasis. Meanwhile, EZH2 undergoes post-translational modifications, including arginine methylation, lysine methylation ( 144 ), and serine/threonine phosphorylation ( 145 ), regulating protein methyltransferase activity ( 146 ), protein stability ( 147 ), or cellular localization ( 148 ), which ultimately affect cancer metastasis. Considering the crucial role of EZH2 in the process of breast cancer metastasis and endocrine resistance ( 138 ), EZH2 inhibition represents a novel treatment option for ARID1A-mutated metastatic breast cancer.…”

Section: Promising Treatment Targetsmentioning

confidence: 99%

ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

et al. 2021

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Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.

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Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis

Cited by 54 publications

References 48 publications

EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis

EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis

LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer

ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

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