Dataset Information

Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL).

ABSTRACT: Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Monoglyceride lipase (MGLL) expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. MGLL-overexpressing clones were analyzed for cell proliferation and cell cycle analysis and in vivo tumorigenesis in nude mice. MGLL was identified as an SND1-interacting protein. Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. MGLL expression was detected in normal human hepatocytes and mouse liver, although it was undetected in human HCC cell lines. An inverse correlation between SND1 and MGLL levels was identified in a human HCC tissue microarray as well as in the TCGA database. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression and a marked decrease in tumor growth in nude mouse xenograft assays. MGLL overexpression inhibited Akt activation that is independent of enzymatic activity of MGLL and overexpression of a constitutively active Akt rescued cells from inhibition of proliferation and restored normal cell cycle progression. This study unravels a novel mechanism of SND1 function and identifies MGLL as a unique tumor suppressor for HCC. MGLL might function as a homeostatic regulator of Akt restraining its activation.

SUBMITTER: Rajasekaran D

PROVIDER: S-EPMC4865920 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein-protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score -10.25 kcal/mol, -9.65 kcal/mol and -9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of -19.25 kcal/mol, -27.03 kcal/mol, -34.6 kcal/mol and -29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was -20.45 kcal/mol, -27.89 kcal/mol, -36.41 kcal/mol and -32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity.

Dataset Information

Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets