The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.
The NAD-dependent histone deacetylase Sirt1 is a negative regulator of T cell activation. Here we report that Sirt1 inhibits T cell activation by suppressing the transcription of Bcl2-associated factor 1 (Bclaf1), a protein required for T cell activation.
Yang et al. demonstrate that Hrd1 plays an important role in DC induction of CD4 T cell immunity. The underlying mechanism involves the ability of Hrd1 to ubiquitinate and degrade BLIMP-1, thus releasing CIITA from transcriptional repression and promoting MHCII expression. As a consequence, Hrd1−/− DCs protect mice from MOG-induced experimental autoimmune encephalomyelitis.
The elevated level of CCNB1 indicates more aggressive cancer and poor prognosis. However, the factors that cause CCNB1 upregulation remain enigmatic. Herein, we identify USP22 as a CCNB1 interactor and discover that both USP22 and CCNB1 are dramatically elevated with a strong positive correlation in colon cancer tissues. USP22 stabilizes CCNB1 by antagonizing proteasome-mediated degradation in a cell cycle-specific manner. Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1. The ubiquitin ligase anaphase-promoting complex (APC/C) targets USP22 for degradation by using the substrate adapter CDC20 during cell exit from M phase, presumably allowing CCNB1 degradation. Finally, we discover that USP22 knockdown leads to slower cell growth and reduced tumor size. Our study demonstrates that USP22 is a CCNB1 deubiquitinase, suggesting that targeting USP22 might be an effective approach to treat cancers with elevated CCNB1 expression.
The NAD-dependent histone deacetylase sirtuin (Sirt)1 is implicated in a wide variety of physiological processes, ranging from tumorigenesis to mitochondrial biogenesis to neuronal development. Recent studies indicate that Sirt1 is a critical regulator of both the innate and adaptive immune response in mice and its altered functions are likely involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. In this review, we highlight the functions of Sirt1 in the immune system focusing on the underlying molecular mechanisms, and the potential of Sirt1 as a therapeutic target for autoimmune diseases.
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