Abstract
Pancreatic cancer is a common malignant tumor with poor prognosis. Recently, cancer stem cells (CSCs) were identified in several solid tumors, including pancreatic cancer. Although accumulating evidence indicates that sirtuin 1 (SIRT1) exerts biological functions in various cancers, how it contributes to tumorigenesis and metastasis of pancreatic cancer, as well as its role in CSCs, is still poorly defined. Here we show that SIRT1 interacts with the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex, which is responsible for H2AK119 monoubiquitination (H2AK119ub1), collaborating as a functional unit. Genome-wide analysis of SIRT1/CUL4B targets identified a cohort of genes, including GRHL3 and FOXO3, critically involved in cell differentiation, growth, and migration. Furthermore, we found that SIRT1 and CUL4B collectively promote the proliferation, autophagy, and invasion of pancreatic cancer cells. Remarkably, we demonstrate that SIRT1/CUL4B promotes CSC-like properties, including increased stemness marker expression and sphere formation. In vivo experiments implied that SIRT1 promoted established tumor xenograft growth, increased tumor-initiating capacity in NOD/SCID mice, and increased CSC frequency. Strikingly, SIRT1 and CUL4B expression is markedly upregulated in a variety of human cancers, including pancreatic cancer. Our data provide a molecular basis for the functional interplay between histone deacetylation and ubiquitination. The results also implicate the SIRT1/CRL4B complex in pancreatic cancer metastasis and stem cell properties, thus supporting SIRT1 as a promising potential target for cancer therapy development.
Highlights
Sirtuins are NAD+ dependent class III histone deacetylase enzymes with lysine deacetylation, ADP-ribosylation, and/or deacylation activities [1]; they are involved in a diverse range of cellular processes, governing both cancer initiation and progression [2]
Whether sirtuins affect stem-like phenotypes in pancreatic cancer cells, FLAG-tagged sirtuin 1 (SIRT1)–7 were stably expressed in PANC-1 cells; using flow cytometry, CD133+ cell content increased in cells overexpressing SIRT1 (Fig. 1B); there was no significant change in other cells
We identified a total of 288 unique promoters targeted by SIRT1 and Cullin 4B (CUL4B), which were classified into various cellular signaling pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway software (Fig. 3D), including Rap1, AMPK, FoxO, Hippo, cell cycle, focal adhesion, and regulating pluripotency of stem cells that are critically involved in tumor initiation and progression
Summary
Sirtuins are NAD+ dependent class III histone deacetylase enzymes with lysine deacetylation, ADP-ribosylation, and/or deacylation activities [1]; they are involved in a diverse range of cellular processes, governing both cancer initiation and progression [2]. SIRT1 plays an important role in tumorigenesis, development, and drug resistance by blocking aging and apoptosis, promoting cell growth and angiogenesis [3]. It has been reported that SIRT1 inhibits apoptosis and senescence and supports the viability, proliferation, and invasion of pancreatic cancer cells [4,5,6]. High SIRT1 levels are associated with poorly differentiated pancreatic ductal carcinomas and poor disease outcomes [7]. SIRT1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive responses to chemotherapy-induced stress, and combination therapy with SIRT1 inhibitor and gemcitabine was shown to have enhanced efficacy for pancreatic carcinoma [8, 9]. Despite the increasing evidence pointing to a critical role for SIRT1 in pancreatic cancer pathogenesis, the detailed mechanisms remain to be established, in the development of pancreatic cancer stem cells (CSCs)
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