SIRT1 regulates the phosphorylation and degradation of P27 by deacetylating CDK2 to promote T-cell acute lymphoblastic leukemia progression

Abstract

Background Despite marked advances in the clinical therapies, clinical outcome of most T-cell acute lymphoblastic leukemia (T-ALL) patients remains poor, due to the high risk of relapse, even after complete remission. Previous studies suggest that the NAD-dependent deacetylase sirtuin 1 (SIRT1) has a dual role in hematologic malignancies, acting as a tumor suppressor or tumor promoter depending on the tumor type. However, little is known about the expression and functions of SIRT1 in T-ALL leukemogenesis. Methods Public RNA-seq data, a Notch1 driven T-ALL mouse model and γ-secretase inhibitor were used to identify SIRT1 expression in T-ALL. We knocked down SIRT1 expression with ShRNAs and assessed the impacts of SIRT1 deficiency on cell proliferation, colony formation, the cell cycle and apoptosis. Transgenic SIRT1 knockout mice were used to determine the function of SIRT1 in vivo. RT-PCR, western blot, co-immunoprecipitation and ubiquitination analyses were used to detect SIRT1, p27 and CDK2 expression and their interactions. Results SIRT1 protein expression was positively correlated with the activation of Notch1. Downregulation of SIRT1 expression suppressed the proliferation and colony formation of T-ALL cell lines, which was reversed by SIRT1 overexpression. SIRT1 silencing prolonged the lifespan of T-ALL model mice. We demonstrated that p27 was involved in the downstream mechanism of cell cycle arrest induced by silencing SIRT1. SIRT1 increased the phosphorylation of p27 on Thr187 by deacetylating CDK2 and enhanced the interaction between p27 and SKP2 leading to the degradation of p27. Conclusion Our findings suggest that SIRT1 is a promising target in T-ALL and offer a mechanistic link between the upregulation of SIRT1 and downregulation of p27.

The sirtuin family in health and disease

“…SIRT1 promotes T-cell acute lymphoblastic leukemia progression by regulating the phosphorylation and degradation of p27 through deacetylating cyclin-dependent kinase 2. 483 SIRT2 is overexpressed in primary acute myeloid leukemia blasts, and SIRT2 activation by nicotinamide phosphoribosyltransferase (NAMPT) reduces proliferation and induces apoptosis in human acute myeloid leukemia, possibly via the Akt/GSK-3β/β-catenin pathway. 335 Inhibition of SIRT2 suppresses the in vitro growth and in vivo engraftment of T-cell acute lymphoblastic leukemia cells via diminished LIM domain only 2 (LMO2) deacetylation.…”

Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells

“…SIRT1 NLSmt exhibited binding activity toward and interactions with CDKs mainly in the cytoplasm SIRT1 has been reported to upregulate CDK1-and CDK2-mediated phosphorylation of substrates via deacetylation of CDK1 and CDK2 [27,28,45,46]. Consistent with this observation, both SIRT1 and SIRT1 NLSmt bound to CDK1 and CDK2, as determined using Co-IP combined with LC-MS/MS (Figure 6A,B), and we further identified their interaction relationships using Co-IP (Figure 6C,D).…”

“…SIRT1 deacetylates lysine 33 of CDK1, thereby promoting the binding interaction of CDK1 and cyclin B [27]. SIRT1 deacetylates CDK2, thereby enhancing the kinase activity of CDK2 toward Thr187 of p27 and leading to subsequent p27 degradation [28].…”

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia

“…With great strides made on oncogene identi cation and immunotherapies, a valuable insight has emerged to guide the management of childhood ALL. Although the therapeutic e cacy and prognosis of childhood ALL has sharply advanced(4), the extremely high incidence and mortality of childhood ALL remain to be a huge challenge in the clinical practice (5,6).…”