Hendi Nagham Nafiz, Nemer Georges
Faculty of Pharmacy, Middle East University, Amman, Jordan.
Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Front Endocrinol (Lausanne). 2025 Jul 18;16:1585859. doi: 10.3389/fendo.2025.1585859. eCollection 2025.
Vitamin D is a pleiotropic hormone essential for bone health and overall physiological function. Despite its significance, vitamin D deficiency remains widespread and is often influenced by genetic factors.
This study investigates the role of , a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. Using CRISPR/Cas9 gene-editing, we generated an knock-in model in HCT116 colorectal cells, which exhibit high endogenous expression, harboring a nonsense variant associated with vitamin D deficiency.
Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, = 0.007) and cancer-related signaling pathways (FC = -1.7, = 0.02). Notably, key differentially expressed genes included upregulated and , alongside downregulated and . Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = -0.37, P = 0.0005). Functionally, deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient overexpression with restoring ABCC2 expression.
These findings establish as a key modulator of vitamin D-related pathways and highlight its potential as a therapeutic target for addressing vitamin D deficiency and associated pathologies, including cancer.
维生素D是一种对骨骼健康和整体生理功能至关重要的多效性激素。尽管其具有重要意义，但维生素D缺乏仍然普遍存在，并且常常受到遗传因素的影响。
本研究调查了一种编码短链脱氢酶/还原酶的基因在维生素D调节和甾醇代谢中的作用。我们使用CRISPR/Cas9基因编辑技术，在高内源性该基因表达且携带与维生素D缺乏相关的无义变异的HCT116结肠癌细胞中构建了该基因敲入模型。
整合的转录组学和蛋白质组学分析显示，甾醇吸收和代谢存在显著失调（倍数变化（FC）=1.8，P=0.007）以及癌症相关信号通路失调（FC=-1.7，P=0.02）。值得注意的是，关键的差异表达基因包括上调的某基因和另一基因，以及下调的某基因和另一基因。蛋白质组分析证实了细胞增殖相关蛋白的改变，包括醛缩酶A表达降低（FC=-0.37，P=0.0005）。在功能上，该基因缺乏使细胞活力降低了53%（P=0.0001），通过瞬时过表达该基因并恢复ABCC2表达可逆转这一效应。
这些发现确立了该基因作为维生素D相关通路的关键调节因子，并突出了其作为解决维生素D缺乏及相关病理（包括癌症）的治疗靶点的潜力。
