Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling

Abstract

Background 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 suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6. Methods Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 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 overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level. Conclusions These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.

Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

“…Furthermore, high expression of SIRT6 was significantly associated with more metastasis and shorter OS and disease-free survival of osteosarcoma patients [ 35 ]. Consistently, the expression of SIRT6 was elevated in cancers compared with normal counterpart cells in the colon, esophagus, melanocytes, thyroid, and lymph node [ 12 , 15 , 19 , 40 , 41 ]. In addition, high expression of SIRT6 was associated with lymph node metastasis of colorectal cancers and thyroid papillary carcinomas [ 12 , 15 ] and was associated with poor prognosis of breast cancer, ovary cancer, gastric cancer, lung cancer, and diffuse large B-cell lymphoma patients [ 14 , 16 – 19 ].…”

“…Consistently, the expression of SIRT6 was elevated in cancers compared with normal counterpart cells in the colon, esophagus, melanocytes, thyroid, and lymph node [ 12 , 15 , 19 , 40 , 41 ]. In addition, high expression of SIRT6 was associated with lymph node metastasis of colorectal cancers and thyroid papillary carcinomas [ 12 , 15 ] and was associated with poor prognosis of breast cancer, ovary cancer, gastric cancer, lung cancer, and diffuse large B-cell lymphoma patients [ 14 , 16 – 19 ]. However, controversially, higher expression of SIRT6 was associated with favorable prognosis of breast cancer patients [ 13 ], and loss of SIRT6 was associated with progression of hepatocellular carcinomas [ 20 ] and colon carcinomas [ 5 ].…”

“…These results suggest that SIRT6-related differences in the prognosis of osteosarcoma patients might be related to SIRT6-mediated resistance to anti-cancer therapy. Supportively, knock-down of SIRT6 sensitized non-small cell lung cancer cells to paclitaxel treatment [ 46 ], and inhibition of SIRT6 sensitized lymphoma cells to doxorubicin [ 19 ]. Furthermore, regarding responsiveness of cancer cells on anti-cancer therapy, one mechanism of interest is the role of the molecules related with the DNA damage repair pathway in therapeutic resistance [ 2 , 24 ].…”

“…Despite the roles of SIRT6 as a sensor to repair DNA damage, higher expression of SIRT6 is related to increased proliferation and invasiveness of cancer cells [ 14 – 16 ]. Furthermore, elevated expression of SIRT6 was associated with shorter survival of cancer patients in the breast, stomach, lung, ovary, and lymphoma [ 14 , 16 – 19 ]. In contrast, loss of SIRT6 is a factor associated with shorter survival of breast and liver cancer patients in other reports [ 13 , 20 ].…”

AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma

“…Formalin-fixed and paraffin-embedded tissue sections obtained from DLBCL and RLH patients were used to perform IHC. The RLH tissues were used as control, as previously described [34,35]. After deparaffinized and hydrated, the antigen was retrieved in 10 mM sodium citrate buffer (pH = 6.0) under high-pressure for 10 min.…”