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Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies
Wei Yu1, Ryan A Denu2, Kimberly A Krautkramer3
1From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry.
Abstract:
B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1α pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1α-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies.
Insights
Sirtuin 3 (SIRT3) acts as a tumor suppressor in B cell malignancies. Lower SIRT3 levels correlate with poor survival, increased reactive oxygen species (ROS), and promote cancer cell proliferation.
Area of Science:
- Mitochondrial biology
- Cancer research
- Biochemistry
Background:
- B cell malignancies are diverse cancers affecting lymphoid tissues and blood.
- Sirtuin 3 (SIRT3) is a mitochondrial deacetylase regulating metabolism and reactive oxygen species (ROS).
- The role of SIRT3 in cancer, as either an oncogene or tumor suppressor, is debated.
Purpose of the Study:
- To investigate the role of SIRT3 in B cell malignancies.
- To determine the impact of SIRT3 expression on patient survival and cancer cell behavior.
- To elucidate the mechanisms underlying SIRT3's function in these cancers.
Main Methods:
- Analysis of SIRT3 protein expression in patient samples (mantle cell lymphoma, chronic lymphocytic leukemia) and cell lines.
- Assessment of mitochondrial protein acetylation (IDH2, SOD2), enzyme activity, and ROS levels.
- Functional studies involving SIRT3 overexpression and depletion in malignant B cell lines.
- Investigation of SIRT3's role in proliferation, Warburg-like phenotype, and response to ROS scavengers or HIF-1α inhibitors.
Main Results:
- Lower SIRT3 protein expression in B cell malignancies correlated with worse overall survival.
- Malignant B cells exhibited reduced SIRT3 expression, increased IDH2/SOD2 hyperacetylation, decreased enzyme activity, and elevated ROS levels.
- SIRT3 overexpression reduced proliferation and the Warburg-like phenotype in a manner dependent on IDH2 and SOD2 deacetylation.
- SIRT3 depletion increased proliferation via ROS-dependent, but not hypoxia-inducible factor-1α-dependent, mechanisms.
Conclusions:
- SIRT3 functions as a tumor suppressor in B cell malignancies.
- Loss of SIRT3 promotes proliferation through ROS-dependent pathways.
- Targeting the SIRT3 pathway may offer a novel therapeutic strategy for B cell malignancies.
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