O-GlcNAcylation and stablization of SIRT7 promote pancreatic cancer progression by blocking the SIRT7-REGγ interaction

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and its dismal prognosis indicates the urgent need to elucidate the potential oncogenic mechanisms. SIRT7 is a classic NAD+-dependent deacetylase that stabilizes the transformed state of cancer cells. However, its functional roles in PDAC are still unclear. Here, we found that SIRT7 expression is upregulated and predicts poor prognosis in PDAC. Then we screened the new interacting proteins of SIRT7 by mass spectrometry and the results showed that SIRT7 can interact with O-GlcNAc transferase (OGT). O-GlcNAcylation stabilizes the SIRT7 protein by inhibiting its interaction with REGγ to prevent degradation, and hyper-O-GlcNAcylation in pancreatic cancer cells leads to hypoacetylation of H3K18 via SIRT7, which promotes transcriptional repression of several tumour suppressor genes. In addition, SIRT7 O-GlcNAcylation at the serine 136 residue (S136) is required to maintain its protein stability and deacetylation ability. In vivo and in vitro experiments showed that blocking SIRT7 O-GlcNAcylation at S136 attenuates tumour progression. Collectively, we demonstrate that O-GlcNAcylation is an important post-translational modification of SIRT7 in pancreatic cancer cells, and elucidating this mechanism of SIRT7 is expected to pave the way for the development of novel therapeutic methods in the future.

Regulation of Life & Death by REGγ

“…By targeting CK1δ, a pathway of REGγ-CK1δ-Mdm2-p53 could be established [ 10 ]. Another recent study of pancreatic ductal adenocarcinoma showed that inhibition of REGγ-mediated SirT7 degradation by O-GlcNAc transferase resulted in repression of tumor suppressor genes and promotion of cancer cells [ 29 ]. Furthermore, Wang et al found that REGγ was overexpressed in over 60% of the 172 colorectal cancer specimens that were analyzed, correlating with increased Yes-Associated Protein (YAP) and p65 levels.…”

Molecular docking‐based virtual screening and dynamics simulation study of novel and potential SIRT7 inhibitors

“…SIRT7 is a family member of the silent information regulator proteins that are described as NAD + -dependent class III histone deacetylases (HDAC III) (Barber et al, 2012). SIRT7 protein can be O-GlcNAcylated, which promotes pancreatic cancer progression by regulating its stability and deacetylation ability (He et al, 2022). Therefore, if a compound was experimentally verified to have a significant deacetylation activity-limiting effect, then it could potentially be used to prevent the development of cancers (Zheng et al, 2020).…”

“…An increasing number of studies have found that SIRT7 is overexpressed in a variety of human malignancies, such as colon, gastric, breast, bladder, ovarian, cervical, hepatocellular, and pancreatic cancers, and its high expression is associated with poor prognosis (Geng et al, 2015; Han et al, 2013, p. 1; He et al, 2022; Kim et al, 2013; Singh et al, 2015; Wang et al, 2015; Yu et al, 2014; Zhang et al, 2015). Geng et al, 2015These findings suggest that it may function as a proto‐oncogene.…”

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

“…A typical example is the notorious cancer promoter, SIRT7, which is a member of the NAD + -dependent deacetylase Sirtuin family [ 120 ]. OGT was detected in complex with SIRT7 in different pancreatic cancer cell lines [ 121 ]. The interaction occurred through the C-terminus of SIRT7 and the TPR region of OGT, inducing O-GlcNAcylation and facilitating the stabilization of SIRT7 by interfering its interaction with REGγ proteasome.…”