Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing
Jing Yang1,2,3,4, Ellen L Weisberg5,6, Shuang Qi1,2
1Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, PR China.
Abstract:
Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.
Insights
Targeting the EZH2 protein, a key driver in certain cancers like diffuse large B-cell lymphoma (DLBCL), may offer a new therapeutic strategy. Inhibiting USP47 promotes the degradation of mutant EZH2, leading to cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Activating mutations in EZH2 (Enhancer of Zeste Homolog 2) drive cancer progression via enzymatic and non-enzymatic functions.
- The EZH2-Y641 mutation is prevalent in diffuse large B-cell lymphoma (DLBCL).
- Current EZH2 inhibitors show limited efficacy due to resistance mechanisms and reliance on EZH2's non-catalytic roles.
Purpose of the Study:
- To identify novel therapeutic targets for EZH2-mutant cancers.
- To investigate the role of USP47 in regulating mutant EZH2.
- To evaluate USP47 inhibition as a potential treatment strategy for DLBCL.
Main Methods:
- Extensive selectivity profiling to identify EZH2 regulators.
- Genetic studies and animal models to validate findings.
- In vitro and in vivo experiments to assess the impact of USP47 inhibition.
Main Results:
- USP47 was identified as a novel regulator of mutant EZH2.
- USP47 inhibition induces mutant EZH2 degradation through ubiquitination.
- Targeting USP47 resulted in the death of mutant EZH2-positive cancer cells in vitro and in vivo.
Conclusions:
- Inhibiting USP47 represents a promising therapeutic strategy for EZH2-mutant cancers.
- Targeting USP47 may overcome resistance to current EZH2 enzymatic inhibitors.
- USP47 inhibition offers a novel treatment approach for DLBCL and other hematologic malignancies with mutant EZH2.
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