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Targeting EZH2 for Cancer Therapy: Progress and Perspective

View Article: PubMed Central - PubMed

ABSTRACT

Enhancer of Zeste Homolog 2 (EZH2) is the core component of the polycomb repressive complex 2 (PRC2), possessing the enzymatic activity in generating di/tri-methylated lysine 27 in histone H3. EZH2 has important roles during early development, and its dysregulation is heavily linked to oncogenesis in various tissue types. Accumulating evidences suggest a remarkable therapeutic potential by targeting EZH2 in cancer cells. The first part reviews current strategies to target EZH2 in cancers, and evaluates the available compounds and agents used to disrupt EZH2 functions. Then we provide insight to the future direction of the research on targeting EZH2 in different cancer types. We comprehensively discuss the current understandings of the 1) structure and biological activity of EZH2, 2) its role during the assembling of PRC2 and recruitment of other protein components, 3) the molecular events directing EZH2 to target genomic regions, and 4) post-translational modification at EZH2 protein. The discussion provides the basis to inspire the development of novel strategies to abolish EZH2-related effects in cancer cells.

No MeSH data available.


Related in: MedlinePlus

Summary of EZH2 targeting strategies. 1) Agents inhibiting the transcription of EZH2 (e.g. SKI-606 and methotrexate), which decrease subsequently the mRNA and protein levels of EZH2, are potential therapeutic drugs to treat EZH2 overexpressing cancer cells. 2) Degradation of EZH2 transcript via RNA interference (e.g. siRNAs or shRNAs) effectively inhibits translation of EZH2 mRNA and induces a significant anticancer effect. Restoring the regulation on EZH2 by miRNAs is another approach to reverse the epigenetic effects of ectopic EZH2. MiRNAs delivered to the cancer cells reduce the EZH2 protein level by either mRNA degradation or inhibiting the translation. 3) 3-Deazaneplanocin A (DZNep) and panobinostat (LBH589) provide a pharmacological approach to deplete the EZH2 protein directly in cancer cells. 4) Small molecule inhibitors (e.g. GSK-126, EPZ-6438, and EI1) specific to EZH2 compete with the methyl-donor S-adenosyl methionine (SAM) for the binding pocket of EZH2. They are highly selective to either wildtype or mutant EZH2 and effectively inhibit trimethylation of H3K27. 5) Silencing target recognition is a critical characteristic of EZH2 prior gene silencing. It was shown that lncRNAs guides EZH2 to dock to the right genomic region. EZH2 silencing can be abolished by abrogating the EZH2-cofactor RNA complex. 6) Phosphorylation of EZH2 protein determines EZH2 activity, stability, and proper targeting. Altering the phosphorylation status of EZH2 theoretically hampers the effect of EZH2 in cancer cells.
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Figure 1: Summary of EZH2 targeting strategies. 1) Agents inhibiting the transcription of EZH2 (e.g. SKI-606 and methotrexate), which decrease subsequently the mRNA and protein levels of EZH2, are potential therapeutic drugs to treat EZH2 overexpressing cancer cells. 2) Degradation of EZH2 transcript via RNA interference (e.g. siRNAs or shRNAs) effectively inhibits translation of EZH2 mRNA and induces a significant anticancer effect. Restoring the regulation on EZH2 by miRNAs is another approach to reverse the epigenetic effects of ectopic EZH2. MiRNAs delivered to the cancer cells reduce the EZH2 protein level by either mRNA degradation or inhibiting the translation. 3) 3-Deazaneplanocin A (DZNep) and panobinostat (LBH589) provide a pharmacological approach to deplete the EZH2 protein directly in cancer cells. 4) Small molecule inhibitors (e.g. GSK-126, EPZ-6438, and EI1) specific to EZH2 compete with the methyl-donor S-adenosyl methionine (SAM) for the binding pocket of EZH2. They are highly selective to either wildtype or mutant EZH2 and effectively inhibit trimethylation of H3K27. 5) Silencing target recognition is a critical characteristic of EZH2 prior gene silencing. It was shown that lncRNAs guides EZH2 to dock to the right genomic region. EZH2 silencing can be abolished by abrogating the EZH2-cofactor RNA complex. 6) Phosphorylation of EZH2 protein determines EZH2 activity, stability, and proper targeting. Altering the phosphorylation status of EZH2 theoretically hampers the effect of EZH2 in cancer cells.

Mentions: gastric, pancreatic, and liver cancers in which EZH2 is overexpressed simultaneously [60-62]. The loss of other microRNAs was also identified as the cause of EZH2 overexpression in other cancer types, which included the loss of miR-26a in rhabdomyosarcoma and nasopharyngeal carcinoma [63, 64], miR-214 in breast cancer [65], miR-31 in melanoma [66] and Let-7 in high grade prostate cancer [67]. In the following paragraphs, we will discuss both the current and prospective strategies to target EZH2 in cancer cells (Fig. 1).


Targeting EZH2 for Cancer Therapy: Progress and Perspective
Summary of EZH2 targeting strategies. 1) Agents inhibiting the transcription of EZH2 (e.g. SKI-606 and methotrexate), which decrease subsequently the mRNA and protein levels of EZH2, are potential therapeutic drugs to treat EZH2 overexpressing cancer cells. 2) Degradation of EZH2 transcript via RNA interference (e.g. siRNAs or shRNAs) effectively inhibits translation of EZH2 mRNA and induces a significant anticancer effect. Restoring the regulation on EZH2 by miRNAs is another approach to reverse the epigenetic effects of ectopic EZH2. MiRNAs delivered to the cancer cells reduce the EZH2 protein level by either mRNA degradation or inhibiting the translation. 3) 3-Deazaneplanocin A (DZNep) and panobinostat (LBH589) provide a pharmacological approach to deplete the EZH2 protein directly in cancer cells. 4) Small molecule inhibitors (e.g. GSK-126, EPZ-6438, and EI1) specific to EZH2 compete with the methyl-donor S-adenosyl methionine (SAM) for the binding pocket of EZH2. They are highly selective to either wildtype or mutant EZH2 and effectively inhibit trimethylation of H3K27. 5) Silencing target recognition is a critical characteristic of EZH2 prior gene silencing. It was shown that lncRNAs guides EZH2 to dock to the right genomic region. EZH2 silencing can be abolished by abrogating the EZH2-cofactor RNA complex. 6) Phosphorylation of EZH2 protein determines EZH2 activity, stability, and proper targeting. Altering the phosphorylation status of EZH2 theoretically hampers the effect of EZH2 in cancer cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997953&req=5

Figure 1: Summary of EZH2 targeting strategies. 1) Agents inhibiting the transcription of EZH2 (e.g. SKI-606 and methotrexate), which decrease subsequently the mRNA and protein levels of EZH2, are potential therapeutic drugs to treat EZH2 overexpressing cancer cells. 2) Degradation of EZH2 transcript via RNA interference (e.g. siRNAs or shRNAs) effectively inhibits translation of EZH2 mRNA and induces a significant anticancer effect. Restoring the regulation on EZH2 by miRNAs is another approach to reverse the epigenetic effects of ectopic EZH2. MiRNAs delivered to the cancer cells reduce the EZH2 protein level by either mRNA degradation or inhibiting the translation. 3) 3-Deazaneplanocin A (DZNep) and panobinostat (LBH589) provide a pharmacological approach to deplete the EZH2 protein directly in cancer cells. 4) Small molecule inhibitors (e.g. GSK-126, EPZ-6438, and EI1) specific to EZH2 compete with the methyl-donor S-adenosyl methionine (SAM) for the binding pocket of EZH2. They are highly selective to either wildtype or mutant EZH2 and effectively inhibit trimethylation of H3K27. 5) Silencing target recognition is a critical characteristic of EZH2 prior gene silencing. It was shown that lncRNAs guides EZH2 to dock to the right genomic region. EZH2 silencing can be abolished by abrogating the EZH2-cofactor RNA complex. 6) Phosphorylation of EZH2 protein determines EZH2 activity, stability, and proper targeting. Altering the phosphorylation status of EZH2 theoretically hampers the effect of EZH2 in cancer cells.
Mentions: gastric, pancreatic, and liver cancers in which EZH2 is overexpressed simultaneously [60-62]. The loss of other microRNAs was also identified as the cause of EZH2 overexpression in other cancer types, which included the loss of miR-26a in rhabdomyosarcoma and nasopharyngeal carcinoma [63, 64], miR-214 in breast cancer [65], miR-31 in melanoma [66] and Let-7 in high grade prostate cancer [67]. In the following paragraphs, we will discuss both the current and prospective strategies to target EZH2 in cancer cells (Fig. 1).

View Article: PubMed Central - PubMed

ABSTRACT

Enhancer of Zeste Homolog 2 (EZH2) is the core component of the polycomb repressive complex 2 (PRC2), possessing the enzymatic activity in generating di/tri-methylated lysine 27 in histone H3. EZH2 has important roles during early development, and its dysregulation is heavily linked to oncogenesis in various tissue types. Accumulating evidences suggest a remarkable therapeutic potential by targeting EZH2 in cancer cells. The first part reviews current strategies to target EZH2 in cancers, and evaluates the available compounds and agents used to disrupt EZH2 functions. Then we provide insight to the future direction of the research on targeting EZH2 in different cancer types. We comprehensively discuss the current understandings of the 1) structure and biological activity of EZH2, 2) its role during the assembling of PRC2 and recruitment of other protein components, 3) the molecular events directing EZH2 to target genomic regions, and 4) post-translational modification at EZH2 protein. The discussion provides the basis to inspire the development of novel strategies to abolish EZH2-related effects in cancer cells.

No MeSH data available.


Related in: MedlinePlus