B-cell Lymphomas Exhibit a Non-Oncogene Addiction to SIRT3

Aberrant proliferation and survival in cancer cells generally depend on specific metabolic pathways. Li and colleagues sought to ascertain the role of sirtuins on mediating cancer-reliant metabolic pathways in diffuse large cell B-cell lymphomas (DLBCL), which are aggressive and highly genetically heterogeneous. An shRNA screen of sirtuins in a cell line panel representing DLBCL subtypes identified SIRT3, which is a nicotinamide adenine dinucleotide–dependent lysine deacetylase that localizes to the mitochondria and deacetylates metabolic enzymes, as the most critical sirtuin for DLBCL cell survival. SIRT3 expression is significantly increased in DLBCL cell lines and patient samples, but not in normal germinal center (GC) B cells, and high SIRT3 levels were associated with poor patient survival. Loss of SIRT3 inhibited proliferation and self-renewal while promoting apoptosis in vitro; further, SIRT3 depletion suppressed tumor growth, but not GC B-cell formation, in vivo. SIRT3 depletion was accompanied by a major reduction of tricarboxylic acid (TCA) cycle metabolites and decreased acetylation of coenzyme A, both of which are known to promote autophagy; similarly, SIRT3-depleted DLBCLs had increased levels of the autophagy markers LC3II/LC3I and p62. Metabolic tracing studies determined SIRT3 depletion impairs glutamine entry into the TCA cycle. Moreover, glutamate dehydrogenase (GDH), a protein that converts glutamate to αKG in order to enter the TCA cycle, was identified as a direct target of SIRT3. GDH overexpression prevented autophagy induction and rescued the proliferative and survival effects of SIRT3 depletion. SIRT3 loss resulted in increased survival and autophagy, as well as reduced tumor growth, in vivo. A mitochondrial targeted class I sirtuin inhibitor, YC8-02, was designed to mainly target SIRT3: YC8-02 induced acetylation of mitochondrial proteins, inhibited GDH activity and proliferation, and induced autophagy in vitro and potently inhibited tumor growth and survival in vivo. These findings identify SIRT3 as a critical driver of lymphomagenesis and a new therapeutic target for DLBCLs.

Li M, Chiang Y-L, Lyssiotis CA, Teater MR, Hong JY, Shen H, et al. Non-oncogene addiction to SIRT3 plays a critical role in lymphomagenesis. Cancer Cell 2019;35:916–31.

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