HDAC1 inhibits CDX2 expression and promotes colorectal cancer cell migration
Abstract
Colorectal cancer (CRC) is the third most common and second deadliest cancer worldwide. The transcription factor caudal type homeobox 2 (CDX2) is essential for intestinal development and epithelial homeostasis and serves as a prognostic marker in CRC. Its loss is associated with epithelial-mesenchymal transition, metastasis, and poor prognosis in CRC. Interestingly, CDX2 is rarely mutated (0.9% allele mutation frequency), suggesting that epigenetic mechanisms contribute to its downregulation. Using a combination of pharmacological screening and genetic approaches in 2D and physiologically relevant 3D culture systems, we identified HDAC1 as a potent transcriptional repressor of CDX2. ChIP-qPCR detected HDAC1 occupancy at a CDX2 promoter region and increased H3K27 acetylation at this region following Quisinostat treatment, supporting this region as the strongest HDAC1-associated regulatory region under the experimental conditions used. Quisinostat restored CDX2 expression by up to 4-fold in CRC cells cultured in both 2D and 3D systems. Moreover, both genetic silencing of HDAC1 and pharmacological HDAC inhibition with Quisinostat significantly reduced CRC cell migration (p ≤ 0.01, nonparametric Mann–Whitney U test), concomitant with increased CDX2 expression. Analysis of publicly available single-cell RNA-sequencing data from CRC patients revealed an inverse association between HDAC1 and CDX2 expression in epithelial tumor cells. Together, our findings identify HDAC1 as an epigenetic regulator of CDX2 expression and show that HDAC1 targeting is accompanied by reduced CRC cell migration. Further mechanistic studies are required to define the contribution of CDX2 to the anti-migratory effects of HDAC1 inhibition, while validation in independent clinical CRC cohorts is needed to confirm the HDAC1-CDX2 relationship at the protein level and establish its prognostic relevance.
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BibTeX
@article{mehmeti2026hdac1,
title = {{HDAC1 inhibits CDX2 expression and promotes colorectal cancer cell migration}},
author = {Rina Mehmeti and José F. Carreño-Martinez and Nils Bodmer and Anna M. Schläfli and Olivier De Wever and Mario P. Tschan and Inti Zlobec},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1821608},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1821608},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HDAC1 inhibits CDX2 expression and promotes colorectal cancer cell migration
AU - Rina Mehmeti
AU - José F. Carreño-Martinez
AU - Nils Bodmer
AU - Anna M. Schläfli
AU - Olivier De Wever
AU - Mario P. Tschan
AU - Inti Zlobec
PY - 2026
DA - 2026/11/09
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1821608
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1821608
AB - Colorectal cancer (CRC) is the third most common and second deadliest cancer worldwide. The transcription factor caudal type homeobox 2 (CDX2) is essential for intestinal development and epithelial homeostasis and serves as a prognostic marker in CRC. Its loss is associated with epithelial-mesenchymal transition, metastasis, and poor prognosis in CRC. Interestingly, CDX2 is rarely mutated (0.9% allele mutation frequency), suggesting that epigenetic mechanisms contribute to its downregulation. Using a combination of pharmacological screening and genetic approaches in 2D and physiologically relevant 3D culture systems, we identified HDAC1 as a potent transcriptional repressor of CDX2. ChIP-qPCR detected HDAC1 occupancy at a CDX2 promoter region and increased H3K27 acetylation at this region following Quisinostat treatment, supporting this region as the strongest HDAC1-associated regulatory region under the experimental conditions used. Quisinostat restored CDX2 expression by up to 4-fold in CRC cells cultured in both 2D and 3D systems. Moreover, both genetic silencing of HDAC1 and pharmacological HDAC inhibition with Quisinostat significantly reduced CRC cell migration (p ≤ 0.01, nonparametric Mann–Whitney U test), concomitant with increased CDX2 expression. Analysis of publicly available single-cell RNA-sequencing data from CRC patients revealed an inverse association between HDAC1 and CDX2 expression in epithelial tumor cells. Together, our findings identify HDAC1 as an epigenetic regulator of CDX2 expression and show that HDAC1 targeting is accompanied by reduced CRC cell migration. Further mechanistic studies are required to define the contribution of CDX2 to the anti-migratory effects of HDAC1 inhibition, while validation in independent clinical CRC cohorts is needed to confirm the HDAC1-CDX2 relationship at the protein level and establish its prognostic relevance.
SN - 2234-943X
ER -