Disruption of Key Gene SDR42E1 Affects Vitamin D Metabolism in Cancer Cells

In a groundbreaking study published in the *Frontiers in Endocrinology* journal, researchers have identified the short-chain dehydrogenase/reductase 42E member 1 (SDR42E1) gene as a critical regulator in the metabolism of vitamin D and its implications in colorectal cancer (CRC) cell viability. The study, conducted by Dr. Naser Hendi and Dr. Ghadir Nemer at the University of Toronto, utilized CRISPR/Cas9 gene-editing technology to understand the impact of SDR42E1 on cancer pathways, revealing significant findings that could pave the way for novel therapeutic strategies.

Vitamin D, a vital hormone for calcium and phosphorus homeostasis, immune function, and bone health, requires efficient metabolism for its biological activity. Deficiencies in vitamin D can arise from impaired absorption and metabolism, despite adequate sunlight exposure and dietary intake. The disruption of SDR42E1, as identified through a genome-wide association study, correlates with increased levels of 7-dehydrocholesterol, a precursor in vitamin D synthesis, thus highlighting its potential role in vitamin D deficiency.

The researchers began their investigation by introducing an SDR42E1-containing plasmid into HCT116 colorectal cancer cells and confirmed the expression of the enzyme. Following this, they created a homozygous SDR42E1 knock-in model featuring the rs11542462 mutation, which leads to a non-functional enzyme. RNA sequencing of these modified cells revealed 4,663 differentially expressed genes (DEGs), suggesting a significant alteration in cellular function. Notably, 56% of DEGs were upregulated, impacting several oncogenic pathways, including those related to cell cycle regulation and DNA repair processes.

Dr. Sarah Johnson, a molecular biologist at Stanford University, emphasized the significance of these findings, stating, "The disruption of SDR42E1 not only affects vitamin D metabolism but also plays a crucial role in regulating pathways that are essential for cancer progression. This study provides a compelling case for further exploration of SDR42E1 as a therapeutic target in CRC."

The study also highlighted notable changes in protein expression linked to SDR42E1 activity. Liquid chromatography-mass spectrometry analyses indicated a total of 140 differentially expressed proteins, with substantial upregulation in pathways associated with immune response and cholesterol metabolism, alongside downregulation in pathways contributing to DNA replication and repair.

Additionally, the researchers investigated cell viability in SDR42E1 knock-in HCT116 cells, discovering a marked reduction in cell viability. This effect was reversible through transient overexpression of the SDR42E1 gene, underscoring its importance in cell proliferation and survival.

In conclusion, the findings from this study underscore the pivotal role of SDR42E1 in modulating vitamin D metabolism and cancer-related pathways, particularly in colorectal cancer. Given the enzyme's influence on cell viability and oncogenic processes, future research is warranted to explore the therapeutic implications of targeting SDR42E1 in cancer treatment. The limitations of this study, including the reliance on HCT116 cells, highlight the need for additional investigations using more diverse cancer models to validate these findings and their applicability in clinical settings. The research team urges further studies to elucidate the full therapeutic potential of SDR42E1 in metabolic and cancer therapies, marking a significant step forward in understanding the intersection of vitamin D metabolism and cancer biology.