FHL1 Downregulation Is Specific to Cancer-Associated Fibroblasts and Linked to Reduced Chromatin Accessibility in Colorectal Cancer.
6 affiliations
- 1Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia.
- 2Laboratory Genetics Specialist, Forensic Medical Services Center, Ministry of Health, Riyadh 13211, Saudi Arabia.
- 3Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia.
- 4Center for Health Research, Northern Border University, Arar 91431, Saudi Arabia.
- 5Department of Anatomic Pathology, Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
- 6Pathology Department, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
Abstract
Background/objectives
Colorectal cancer (CRC) is among the most diagnosed malignancies and is a leading cause of cancer-related deaths globally. Beyond canonical CRC driver mutations, additional molecular alterations such as dysregulated gene expression and epigenetic reprogramming shape the disease behavior and may represent potential candidate biomarkers. The Four and a Half LIM domain (FHL) family, specifically FHL1, has been implicated as a tumor suppressor in CRC epithelial cells. However, FHL1 expression is reduced in CRC and whether this reduction in heterogenous tumors is cell type-specific remains unknown.Methods
In this study, we integrated bulk genomic, transcriptomic and survival data from the cancer genome atlas (TCGA) with publicly available single-cell transcriptomic and epigenomic datasets to identify where and how FHL1 expression is dysregulated in CRC.Results
While somatic mutations of FHL family genes are infrequent and non-recurrent, downregulation of FHL1 in CRC tissue is evident and shows a modest association with longer survival that is not independent of clinical factors. Notably, single-cell analysis across three independent studies revealed that FHL1 expression is largely restricted to fibroblasts and is specifically downregulated in cancer-associated fibroblasts (CAFs). FHL1 expression is inversely associated with activated CAF markers FAP and ACTA2, while normal fibroblast markers WNT2B and RSPO3 demonstrate a similar expression pattern to FHL1. Finally, chromatin accessibility at the FHL1 promoter was substantially reduced in CAFs relative to pre-CAFs and normal fibroblasts.Conclusions
Our study identifies that FHL1 downregulation is specific to CAFs in CRC and is accompanied by chromatin inaccessibility within the FHL1 promoter in CAFs.
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BibTeX
@article{alqasem2026fhl1,
title = {{FHL1 Downregulation Is Specific to Cancer-Associated Fibroblasts and Linked to Reduced Chromatin Accessibility in Colorectal Cancer.}},
author = {Abdullah A Alqasem and Waad Al-Burayk and Muneira Habjar and Batla Aldawsari and Alanoud Almansour and Mohammad A Alahmari and Adel M Alqarni and Helal G Alanazi and Mohammed M Alruwaili and Emad Alqassim and Ahmed Rokan and Abdulrahman A Alahmari},
journal = {Genes},
year = {2026},
month = sep,
doi = {10.3390/genes17101210},
url = {https://europepmc.org/article/MED/42938326},
note = {CC BY},
}
RIS
TY - JOUR
TI - FHL1 Downregulation Is Specific to Cancer-Associated Fibroblasts and Linked to Reduced Chromatin Accessibility in Colorectal Cancer.
AU - Abdullah A Alqasem
AU - Waad Al-Burayk
AU - Muneira Habjar
AU - Batla Aldawsari
AU - Alanoud Almansour
AU - Mohammad A Alahmari
AU - Adel M Alqarni
AU - Helal G Alanazi
AU - Mohammed M Alruwaili
AU - Emad Alqassim
AU - Ahmed Rokan
AU - Abdulrahman A Alahmari
PY - 2026
DA - 2026/09/29
JO - Genes
DO - 10.3390/genes17101210
UR - https://europepmc.org/article/MED/42938326
AB - Background/objectives Colorectal cancer (CRC) is among the most diagnosed malignancies and is a leading cause of cancer-related deaths globally. Beyond canonical CRC driver mutations, additional molecular alterations such as dysregulated gene expression and epigenetic reprogramming shape the disease behavior and may represent potential candidate biomarkers. The Four and a Half LIM domain (FHL) family, specifically FHL1, has been implicated as a tumor suppressor in CRC epithelial cells. However, FHL1 expression is reduced in CRC and whether this reduction in heterogenous tumors is cell type-specific remains unknown.Methods In this study, we integrated bulk genomic, transcriptomic and survival data from the cancer genome atlas (TCGA) with publicly available single-cell transcriptomic and epigenomic datasets to identify where and how FHL1 expression is dysregulated in CRC.Results While somatic mutations of FHL family genes are infrequent and non-recurrent, downregulation of FHL1 in CRC tissue is evident and shows a modest association with longer survival that is not independent of clinical factors. Notably, single-cell analysis across three independent studies revealed that FHL1 expression is largely restricted to fibroblasts and is specifically downregulated in cancer-associated fibroblasts (CAFs). FHL1 expression is inversely associated with activated CAF markers FAP and ACTA2, while normal fibroblast markers WNT2B and RSPO3 demonstrate a similar expression pattern to FHL1. Finally, chromatin accessibility at the FHL1 promoter was substantially reduced in CAFs relative to pre-CAFs and normal fibroblasts.Conclusions Our study identifies that FHL1 downregulation is specific to CAFs in CRC and is accompanied by chromatin inaccessibility within the FHL1 promoter in CAFs.
SN - 2073-4425
ER -