SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy

Abstract

SIRT6, NAD+-dependent deacetylase sirtuin 6, has recently shown to suppress tumor growth in several types of cancer. Colon cancer is a challenging carcinoma associated with high morbidity and death. However, whether SIRT6 play a direct role in colon tumorigenesis and the underlying mechanism are not understood. Methods : To investigate the role of SIRT6 in colon cancer, we firstly analyzed the specimens from 50 colorectal cancer (CRC) patients. We generated shSIRT6 LoVo cells and xenograft mouse to reveal the essential role of SIRT6 in cell apoptosis and tumor growth. To explore the underlying mechanism of SIRT6 regulation, we performed FRET and real-time fluorescence imaging in living cells, real-time PCR, immunoprecipitaion, immunohistochemistry, flow cytometry and luciferase reporter assay. Results : The expression level of SIRT6 in patients' specimens is lower than that of normal controls, and patients with higher SIRT6 level have a better prognosis. Here, we identified that transcriptional factor FoxO3a is a direct up-stream of SIRT6 and positively regulated SIRT6 expression, which in turn, promotes apoptosis by activating Bax and mitochondrial pathway. Functional studies reveal that Akt inactivation increases FoxO3a activity and augment its binding to SIRT6 promoter, leading to elevated SIRT6 expression. Knocking down SIRT6 abolished apoptotic responses and conferred resistance to the treatment of BKM120. Combinational therapies with conventional drugs showed synergistic chemosensitization, which was SIRT6-dependent both in vitro and in vivo . Conclusion : The results uncover SIRT6 as a new potential biomarker for colon cancer, and its unappreciated mechanism about transcription and expression via Akt/FoxO3a pathway.

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

“…it was demonstrated that FOXO3a functioned as a direct transcription factor that targeted the promoter of SIRT6. Recently, a similar mechanism has also been reported in a study in colon cancer (48).…”

ROS-Mediated Apoptotic Cell Death of Human Colon Cancer LoVo Cells by Milk δ-Valerobetaine

“…Moreover, SIRT6 downregulation in colon cancer tissues and different colon cancer cell lines negatively correlated with the overall survival of patients through the regulation of PTEN/AKT signaling pathway 21 . A more recent study performed on 50 patients with CRC showed a lower expression of SIRT6 compared to normal controls, whereas patients with higher SIRT6 level had a better prognosis 44 . However, the mechanism through which SIRT6 controls cancer progression is intriguing and, depending on the biologic context, both increased and reduced SIRT6 activity could be exploitable by cancer cells 14,17,45 .…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. SIRT6 can drive apoptosis by deacetylating key cell signaling molecules, such as KU70, Bax, and P53, in response to DNA damage and oxidative stress [70,111,112].…”