SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model
IntroductionVitamin 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. MethodsThis study investigates the role of SDR42E1, a gene encoding a short-chain...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2025.1585859/full |
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| author | Nagham Nafiz Hendi Nagham Nafiz Hendi Georges Nemer Georges Nemer |
| author_facet | Nagham Nafiz Hendi Nagham Nafiz Hendi Georges Nemer Georges Nemer |
| author_sort | Nagham Nafiz Hendi |
| collection | DOAJ |
| description | IntroductionVitamin 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. MethodsThis study investigates the role of SDR42E1, a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. 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.ResultsIntegrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, P = 0.007) and cancer-related signaling pathways (FC = −1.7, P = 0.02). Notably, key differentially expressed genes included upregulated LRP1B and ABCC2, alongside downregulated WNT16 and SLC7A5. Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = −0.37, P = 0.0005). Functionally, SDR42E1 deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient SDR42E1 overexpression with restoring ABCC2 expression. ConclusionThese 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. |
| format | Article |
| id | doaj-art-bc45fdf102e044aaa599a8887d466f6a |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-bc45fdf102e044aaa599a8887d466f6a2025-08-20T03:51:25ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-07-011610.3389/fendo.2025.15858591585859SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro modelNagham Nafiz Hendi0Nagham Nafiz Hendi1Georges Nemer2Georges Nemer3Faculty of Pharmacy, Middle East University, Amman, JordanDivision of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, QatarDivision of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, QatarDepartment of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, LebanonIntroductionVitamin 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. MethodsThis study investigates the role of SDR42E1, a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. 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.ResultsIntegrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, P = 0.007) and cancer-related signaling pathways (FC = −1.7, P = 0.02). Notably, key differentially expressed genes included upregulated LRP1B and ABCC2, alongside downregulated WNT16 and SLC7A5. Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = −0.37, P = 0.0005). Functionally, SDR42E1 deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient SDR42E1 overexpression with restoring ABCC2 expression. ConclusionThese 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.https://www.frontiersin.org/articles/10.3389/fendo.2025.1585859/fullvitamin D regulationSDR42E1endocrine disordersgenetics in endocrinologyprecision medicine |
| spellingShingle | Nagham Nafiz Hendi Nagham Nafiz Hendi Georges Nemer Georges Nemer SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model Frontiers in Endocrinology vitamin D regulation SDR42E1 endocrine disorders genetics in endocrinology precision medicine |
| title | SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model |
| title_full | SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model |
| title_fullStr | SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model |
| title_full_unstemmed | SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model |
| title_short | SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model |
| title_sort | sdr42e1 modulates vitamin d absorption and cancer pathogenesis insights from an in vitro model |
| topic | vitamin D regulation SDR42E1 endocrine disorders genetics in endocrinology precision medicine |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1585859/full |
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