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Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.ORCID iD: 0000-0002-0045-2133
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.ORCID iD: 0000-0002-6549-086x
Department of Biomedicine, School of Health Sciences, University of Skövde, Skövde, Sweden.
Jönköping University, School of Health and Welfare, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health and Welfare, HHJ. Biomedical Platform.
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2021 (English)In: Open Medicine (Poland), ISSN 2391-5463, Vol. 16, no 1, p. 640-650Article in journal (Refereed) Published
Abstract [en]

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression when bound to specific DNA sequences. Crosstalk between steroid NR systems has been studied for understanding the development of hormone-driven cancers but not to an extent at a genetic level. This study aimed to investigate crosstalk between steroid NRs in conserved intron and exon sequences, with a focus on steroid NRs involved in prostate cancer etiology. For this purpose, we evaluated conserved intron and exon sequences among all 49 members of the NR Superfamily (NRS) and their relevance as regulatory sequences and NR-binding sequences. Sequence conservation was found to be higher in the first intron (35%), when compared with downstream introns. Seventy-nine percent of the conserved regions in the NRS contained putative transcription factor binding sites (TFBS) and a large fraction of these sequences contained splicing sites (SS). Analysis of transcription factors binding to putative intronic and exonic TFBS revealed that 5 and 16%, respectively, were NRs. The present study suggests crosstalk between steroid NRs, e.g., vitamin D, estrogen, progesterone, and retinoic acid endocrine systems, through cis-regulatory elements in conserved sequences of introns and exons. This investigation gives evidence for crosstalk between steroid hormones and contributes to novel targets for steroid NR regulation.

Place, publisher, year, edition, pages
Walter de Gruyter, 2021. Vol. 16, no 1, p. 640-650
Keywords [en]
conserved sequences, crosstalk, nuclear receptor binding domains, splicing sites, transcription factor binding sites
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:hj:diva-52373DOI: 10.1515/med-2021-0264ISI: 000645596800001PubMedID: 33954257Scopus ID: 2-s2.0-85104533727Local ID: GOA;;738320OAI: oai:DiVA.org:hj-52373DiVA, id: diva2:1548613
Available from: 2021-05-03 Created: 2021-05-03 Last updated: 2022-03-07Bibliographically approved
In thesis
1. Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
Open this publication in new window or tab >>Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The genetic background together with environmental factors and lifestyle are key contributors to the health of an individual. Genetic background is inherited and irreversible unless mutations occur. However, lifestyle habits (i.e., diet, stress, physical activity, smoking, and alcohol consumption) are modifiable factors that contribute to health or disease by affecting methylation of DNA, which regulates transcription of genes.

One of the most relevant lifestyle habits for health is maintaining adequate vitamin D levels in the body as vitamin D promotes calcium and phosphate absorption, supports the nervous and immune system function, and protects bone and muscle structure. Extreme low levels of vitamin D, vitamin D deficiency, has become a global public health concern, especially in the elderly population as vitamin D deficiency can lead to several health problems such as bone fracture, decreased muscle strength, cardiovascular and autoimmune diseases, depression, and breast, pancreatic, and prostate cancer.

Prostate cancer is an uncontrolled growth of cells within the prostate gland in the male reproductive system. Human prostate carcinomas are sensitive to androgens, and hormonal ablation therapy gives a temporary remission, followed by a relapse to an androgen-insensitive state. This indicates that steroid hormones, especially androgens, play a significant role in human prostatic carcinogenesis. The molecular effect of vitamin D as a steroid hormone and which steroid hormone receptor (SHR) mediates this effect are not fully understood.

This research project aims to increase our knowledge about SHRs, primarily the vitamin D receptors, in both health and disease, focusing on genomic, epigenomic, and transcriptomic perspectives in healthy elderly individuals and prostate cancer cells.

The results from the studies in this thesis could help us understand the importance of a healthy lifestyle, which includes vitamin D for health, where we found specific methylation markers involved in the down-regulation of cancer pathways that are associated with high physical activity and vitamin D supplementation. We have further confirmed that SHRs rarely work in isolation but rather as a crosstalk at the genomic level to regulate their transcription. Hopefully, this will help clarify the modulation of transcriptional responses in SHRs and explain the development of steroid hormone-dependent cancers such as prostate cancer. Last, but not least, we revealed that genetic and transcriptional markers are associated with the putative vitamin D receptor the protein disulfide isomerase family A member 3 (PDIA3). The genetic markers were detected in a healthy elderly population under vitamin D supplementation. The transcriptional markers, PDIA3, and a novel discovered isoform of PDIA3 (PDIA3N) were related to the androgen and cancer stage of prostate cancer cells and therefore are proposed as candidate markers for clinical diagnosis of prostate cancer.

Altogether, these findings support the relevance of studying vitamin D and steroid hormone receptors, especially the PDIA3 receptor, to understand some of the factors related to healthy aging and the etiology and progression of prostate cancer.

Place, publisher, year, edition, pages
Jönköping: Jönköping University, School of Health and Welfare, 2022. p. 89
Series
Hälsohögskolans avhandlingsserie, ISSN 1654-3602 ; 111
Keywords
vitamin D, steroid hormone receptors, lifestyle, methylation, SNPs, healthy elderly, prostate cancer cells, crosstalk, PDIA3
National Category
Cancer and Oncology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:hj:diva-56001 (URN)978-91-88669-10-0 (ISBN)
Public defence
2022-04-07, Forum Humanum, School of Health and Welfare, Jönköping, 13:00 (English)
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Available from: 2022-03-07 Created: 2022-03-07 Last updated: 2022-08-16Bibliographically approved

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Diaz Cruz, Maria AraceliLundh, DanKarlsson, SandraFaresjö, Maria

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