Sirt6 Oncogene Mediates PI3K/Akt Signaling Activation in Diffuse Large B-Cell Lymphoma

ABSTRACT: Purpose:Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppress and augment tumor growth. This experiment aimed to document the Sirt6 expression and functions in diffuse large B-cell lymphoma (DLBCL). Methods:Immunohistochemistry was conducted to assess the expression of Sirt6 on paraffin-embedded tissues from 70 DLBCL patients and 35 reactive hyperplasia patients with informed contents. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. shSirt6 transfected or shControl transfected LY1 cell samples were performed RNA sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID-Beige mice to establish xenograft models. Results:Sirt6 is found to be highly expressed and predictive of negative prognoses in DLBCL. Sirt6-deprived DLBCL cells demonstrated augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation and were noted to have arrested cell cycle progression between the G2 and M phases. In accordance with the gene set enrichment analysis (GSEA) according to RNA-sequencing, PI3K signaling along with phosphorylation of its downstream targets (including mTOR and AKT) was reduced upon Sirt6 downregulation. Xenograft models that were infected with Sirt6-knockdown vectors demonstrated suppressed tumor growth and lower rates of c-Myc/Ki-67 staining. Conclusion: These findings provide mechanistic insights into the oncogenic activity of Sirt6 for the first time.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135914 | GEO | 2019/08/17

REPOSITORIES: GEO