Physiology Area, Department of Basic Health Sciences. Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid, Spain.
Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-Universidad Autónoma de Madrid, Spain.
Int J Biol Sci. 2024 Oct 7;20(14):5495-5509. doi: 10.7150/ijbs.95875. eCollection 2024.
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 D (1,25(OH)D 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)D-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)D. 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.
癌症的发生和发展是由遗传和表观遗传改变引起的，这些改变是由环境和内源性因素相互作用导致的异常细胞信号导致的。结直肠癌（CRC）与 Wnt/β-catenin 通路的异常激活有关，其主要特征是乙酰化β-catenin 在结肠上皮细胞中的核积累。核β-catenin 作为转录共激活因子，靶向参与细胞增殖和侵袭的基因。1α,25-二羟维生素 D（1,25(OH)D 或骨化三醇）是维生素 D 的活性形式，通过与其高亲和力受体 VDR 结合，拮抗 Wnt/β-catenin 的过度激活。在这里，我们揭示了 1,25(OH)D 结合的 VDR 激活沉默信息调节因子 1（SIRT1），导致 β-catenin 去乙酰化和核排斥，下调其促肿瘤靶基因，并抑制人结肠癌细胞增殖。值得注意的是，正交 SIRT1 激活模拟了β-catenin 的核排斥，而 SIRT1 抑制阻断了 1,25(OH)D 的作用。因此，SIRT1 成为维生素 D 预防 CRC 的关键介导因子。这里揭示的 Wnt 和 SIRT1 之间的相互负反馈环代表了 CRC 的一个重要替代靶标。由于β-catenin 的核定位是 CRC 的关键驱动因素，需要其乙酰化，因此我们为流行病学证据提供了一个机制基础，该证据将维生素 D 缺乏与增加的 CRC 风险和死亡率联系起来。
