Leptin-induced SIRT1 expression: a potential linker between obesity and cancer

抄録

Leptin, a representative adipokine secreted from the white adipose tissue, is considered as a potential linker between obesity and cancer. SIRT1 is an NAD⁺-dependent histone/protein deacetylase speculated to function as an oncogene. This prompted us to investigate the role of SIRT1 in leptin-induced colon carcinogenesis. In the present study, we found that leptin signaling-defective ob/ob and db/db mice showed lower expression of SIRT1 in colon tissues compared with leptin signaling-intact C57BL/6J mice. Moreover, leptin induced upregulation of SIRT1 in human colon cancer (HCT-116) cells. Leptin promoted migration and invasion of HCT-116 cells and tumor growth in the xenograft assay, which was abrogated by treating with a SIRT1 inhibitor sirtinol, suggesting that SIRT1 accounts for leptin-induced colon carcinogenesis. Notably, leptin-induced SIRT1 expression was regulated by the redox-sensitive transcription factor NF-E2-related factor 2 (Nrf2). Leptin stimulated nuclear accumulation of Nrf2 as well as its direct interaction with antioxidant response elements located in the SIRT1 promoter. We also found that siRNA knockdown of Nrf2 abrogated leptin-induced SIRT1 expression. Moreover, SIRT1 was significantly reduced in colon tissues of Nrf2-null mice, lending further support to Nrf2-dependent SIRT1 expression. Based on the observations from using N-acetylcysteine and AG490, the ROS-JAK2-STAT3 axis may be involved in leptin-induced Nrf2 activation. The expression of leptin, Nrf2 and SIRT1 was coordinately increased in human colon tumor tissues, providing substantial evidence. In conclusion, the obese protein leptin might stimulate colon tumor promotion as well as progression via the Nrf2-dependent SIRT1 overexpression.