Vitamin D is not only an essential nutrient but is also the precursor of the hormone calcitriol, which regulates the uptake of phosphate and calcium necessary for bones by the intestines, as well as cell growth and the proper function of muscles, nerve cells, and the immune system.
In vitro studies by researchers at the Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, and at the Faculty of Pharmacy, Middle East University, Amman, have now found that a gene, SDR42E1, is crucial for taking up vitamin D from the gut and further metabolizing it. The team used CRISPR-Cas9 technology to introduce a mutant form of the gene into a cancer cell line that normally demonstrates high SDR42E1 expression and found that introducing the mutated gene resulted in a dramatic decrease in cell viability, and impacted on the expression levels of thousands of downstream genes.
Professor and associate dean for research, Georges Nemer, PhD, and Nagham Nafiz Hendi, PhD, suggest that their findings could have possible applications in precision medicine, including cancer therapy. “Here we show that blocking or inhibiting SDR42E1 may selectively stop the growth of cancer cells,” said Nemer, who is corresponding author of the published paper in Frontiers in Endocrinology (“SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model.”) In their paper, Nemer and Hendi concluded that their findings “… establish SDR42E1 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.”
Vitamin D is a vital fat-soluble nutrient that is crucial for calcium and phosphorus homeostasis, bone health, and immune function, the authors explained. But despite the availability of dietary sources and sunlight exposure, deficiencies can arise, resulting from impaired absorption and metabolism. “Vitamin D is a pleiotropic hormone essential for bone health and overall physiological function,” they wrote. “Despite its significance, vitamin D deficiency remains widespread and is often influenced by genetic factors.”
The newly reported study was inspired by earlier research that had found a specific mutation in the SDR42E1 gene on chromosome 16 to be associated with vitamin D deficiency. The mutation caused the protein to be cut short, rendering it inactive.
Nemer and colleagues, for their study in Frontiers in Endocrinology, used CRISPR/Cas9 gene editing to transform the active form of SDR42E1 in a line of cells—HCT116—from a patient with colorectal cancer, into its inactive form. In HCT116 cells, the expression of SDR42E1 is usually abundant, suggesting that the protein is essential for their survival.
“Using CRISPR/Cas9 gene-editing, we generated an SDR42E1 knock-in model in HCT116 colorectal cells, which exhibit high endogenous SDR42E1 expression, harboring a nonsense variant associated with vitamin D deficiency,” the investigators further explained. The team then carried out transcriptomic and proteomic analyses to characterize the downstream molecular alterations resulting from SDR42E1 disruption.
The researchers found that introducing the faulty SDR42E1 gene copy resulted in a 53% drop in cancer cell viability. No fewer than 4,663 “downstream” genes changed their expression levels, suggesting that SDR42E1 is a crucial molecular switch in many reactions necessary for the health of cells. Many of these genes are normally involved in cancer-related cell signaling and the absorption and metabolism of cholesterol-like molecules, consistent with the central role of SDR42E1 in calcitriol synthesis.
“Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism … and cancer-related signaling pathways,” the investigators noted. “The findings advance our understanding of the molecular mechanisms underpinning vitamin D deficiency and highlight SDR42E1 as a potential molecular target.”
The results suggest that inhibiting the gene can selectively kill cancer cells, while leaving neighboring cells unharmed. “Overall, our study elucidates valuable insights into the role of SDR42E1 in vitamin D metabolism and sterol processing, as well as its broader implications in cancer-related pathways,” the team continued. “Our results open new potential avenues in precision oncology, though clinical translation still requires considerable validation and long-term development,” added Hendi.
Starving selected cells of vitamin D is not the only possible application that immediately sprang to the mind of the researchers. The present results suggest that SDR42E1 cuts two ways: artificially “dialing up” levels of SDR42E1 in local tissues through gene technology might likewise be beneficial, leveraging the many known health effects of calcitriol.
“Because SDR42E1 is involved in vitamin D metabolism, we could also target it in any of the many diseases where vitamin D plays a regulatory role,” said Nemer. “For example, nutrition studies have indicated that the hormone can lower the risk of cancer, kidney disease, and autoimmune and metabolic disorders.” However, added Hendi, “… such broader applications must be done with caution, as long-term effects of SDR42E1 on vitamin D balance remain to be fully understood.”
In their paper, the team concluded, “Importantly, this work opens avenues for exploring SDR42E1 modulation as a therapeutic strategy to enhance vitamin D bioavailability and potentially counteract tumorigenic processes associated with sterol dysregulation.”
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