Vitamin D is not only an essential nutrient, but also the precursor of the hormone calcitriol, indispensable for health: it 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.
Now, researchers have shown for the first time in Frontiers in Endocrinology that a particular gene, called SDR42E1, is crucial for taking up vitamin D from the gut and further metabolizing it – a discovery with many 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 Dr Georges Nemer, a professor and associate dean for research at the University of College of Health and Life Sciences at Hamad Bin Khalifa University in Qatar, and the study's corresponding author.
Faulty copy
Nemer and colleagues were 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.
The researchers used CRISPR/Cas9 gene editing to transform the active form of SDR42E1 in a line of cells from a patient with colorectal cancer, called HCT116, into its inactive form. In HCT116 cells, the expression of SDR42E1 is usually abundant, suggesting that the protein is essential for their survival.
Once the faulty SDR42E1 copy had been introduced, the viability of the cancer cells plummeted by 53%. 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.
These results suggest that inhibiting the gene can selectively kill cancer cells, while leaving neighboring cells unharmed.
Cuts two ways
"Our results open new potential avenues in precision oncology, though clinical translation still requires considerable validation and long-term development," said Dr Nagham Nafiz Hendi, a professor at Middle East University in Amman, Jordan, and the study's first author.
But 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."
Dr. Georges Nemer, Hamad Bin Khalifa University
"For example, nutrition studies have indicated that the hormone can lower the risk of cancer, kidney disease, and autoimmune and metabolic disorders."
"But such broader applications must be done with caution, as long-term effects of SDR42E1 on vitamin D balance remain to be fully understood," warned Hendi.
New cellular entry pathway improves gene therapy outcomes