Colorectal cancer-associated SNP rs17042479 is involved in the regulation of NAF1 promoter activity

Josephine B Olsson; Marietta B Gugerel; Stine B Jessen; Jannie Jørgensen; Ismail Gögenur; Camilla Hansen; Lene T Kirkeby; Jørgen Olsen; Ole B V Pedersen; Peter M Vestlev; Katja Dahlgaard; Jesper T Troelsen

doi:10.1371/journal.pone.0274033

Colorectal cancer-associated SNP rs17042479 is involved in the regulation of NAF1 promoter activity

PLoS One. 2022 Sep 6;17(9):e0274033. doi: 10.1371/journal.pone.0274033. eCollection 2022.

Authors

Affiliations

¹ Department of Science and Environment, Roskilde University, Roskilde, Denmark.
² Department of Clinical Immunology, Zealand University Hospital, Naestved, Denmark.
³ Center for Surgical Science, Enhanced Perioperative Oncology (EPeOnc) Consortium, Department of Surgery, Zealand University Hospital, Køge, Denmark.
⁴ Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
⁵ Department of Oncology, Roskilde Hospital, Roskilde, Denmark.

Abstract

A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk locus at 4q32.2 is unknown. We investigated the promoter activity of NAF1 and FSTL5 and analyzed the risk locus at 4q32.2 as gene regulatory region. Our results showed that the activity of the FSTL5 promoter was low compared to the NAF1 promoter. Analyses of the NAF1 promoter in conjunction with the region containing the risk locus at 4q32.2 showed that the region functions as gene regulatory region with repressor activity on NAF1 promoter activity. The SNP rs17042479(G) increased the repressor effect of the region. CRC patients' biopsies were genotyped for SNP rs17042479(A/G), and NAF1 expression profiles were examined. We found an association between SNP rs17042479(G), cancer stage and tumor location. Additionally, patients with SNP rs17042479(G) showed lower NAF1 expression in comparison to patients with SNP rs17042479(A) in tumor tissue and the NAF1 expression in tumor tissue was lower compared to healthy tissue. The results in the study imply that reduced NAF1 expression in the tumor contribute to a more aggressive phenotype. Furthermore, this study suggests that the SNP rs17042479(G) change the expression of NAF1 and thereby increases the risk of developing CRC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / genetics
Genotype
Humans
NFI Transcription Factors* / genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Ribonucleoproteins / genetics

Substances

NAF1 protein, human
NFI Transcription Factors
Ribonucleoproteins

Grants and funding

OBVP and JBO received funding from Region Sjællands Sundhedsvidenskabelige Forskningsfond (RSSF) (R19A255B83). JBO received funding from Region Syddanmarks og Region Sjællands fælles forskningspulje (A170). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.