SIRT1 Mediates the Antagonism of Wnt/β-Catenin Pathway by Vitamin D in Colon Carcinoma Cells.

Abstract

Cancer initiation and progression result from genetic and epigenetic alterations caused by interactions between environmental and endogenous factors leading to aberrant cell signalling. Colorectal cancers (CRC) are linked to abnormal activation of the Wnt/β-catenin pathway, whose key feature is the nuclear accumulation of acetylated β-catenin in colon epithelial cells. Nuclear β-catenin acts as a transcriptional co-activator, targeting genes involved in cell proliferation and invasion. 1α,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃ or calcitriol), the active form of vitamin D, antagonizes Wnt/β-catenin over-activation by engaging its high affinity receptor, VDR. Here we unveil that 1,25(OH)₂D₃-bound VDR activates Silent Information Regulator of Transcription, sirtuin 1 (SIRT1), leading to β-catenin deacetylation and nuclear exclusion, downregulation of its pro-tumourigenic target genes and inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation mimics nuclear exclusion of β-catenin while SIRT1 inhibition blocks the effects of 1,25(OH)₂D₃. Thus, SIRT1 emerges as a crucial mediator in the protective action of vitamin D against CRC. The mutual negative feedback loop unveiled here between Wnt and SIRT1 represents an important surrogate target in CRC. Since nuclear localisation of β-catenin is a critical driver of CRC that requires its acetylation, we provide a mechanistic foundation for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.