Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2023; 15(12): 2150-2168
Published online Dec 15, 2023. doi: 10.4251/wjgo.v15.i12.2150
Association between heat shock factor protein 4 methylation and colorectal cancer risk and potential molecular mechanisms: A bioinformatics study
Wen-Jing Zhang, Ke-Lin Yue, Jing-Zhai Wang, Yu Zhang
Wen-Jing Zhang, Department of Medical Oncology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
Ke-Lin Yue, Jing-Zhai Wang, Yu Zhang, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
Author contributions: Zhang WJ and Zhang Y conceived and designed the experiments; Zhang WJ, Yue KL, and Wang JZ analyzed the data; Zhang Y contributed to the data curation; Zhang WJ wrote-original draft preparation; Yue KL, Wang JZ, and Zhang Y participated in the writing-review and editing.
Supported by National Natural Science Foundation of China, No. 82260601; Joint Foundation of Kunming Medical University and Yunnan Provincial Science and Technology Department, No. 202201AY070001-256; Grant for Clinical Medical Center of Yunnan Provincial Health Commission, No. 2021LCZXXF-XH03; and Young Academic Talents Cultivation Foundation of Yunnan Province, No. 202205AC160070.
Institutional review board statement: This study did not involve any animal and human experimentation.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yu Zhang, MD, PhD, Associate Professor, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, Yunnan Province, China. yuzhang320@sina.com
Received: July 28, 2023
Peer-review started: July 28, 2023
First decision: September 26, 2023
Revised: October 16, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 15, 2023
Processing time: 139 Days and 3.5 Hours
Abstract
BACKGROUND

We previously demonstrated that heat shock factor protein 4 (HSF4) facilitates colorectal cancer (CRC) progression. DNA methylation, a major modifier of gene expression and stability, is involved in CRC development and outcome.

AIM

To investigate the correlation between HSF4 methylation and CRC risk, and to uncover the underlying molecular mechanisms.

METHODS

Differences in β values of HSF4 methylation loci in multiple malignancies and their correlation with HSF4 mRNA expression were analyzed based on Shiny Methylation Analysis Resource Tool. HSF4 methylation-related genes were identified by LinkedOmics in CRC, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Protein-protein interaction network of HSF4 methylation-related genes was constructed by String database and MCODE algorithm.

RESULTS

A total of 19 CpG methylation loci were identified in HSF4, and their β values were significantly increased in CRC tissues and exhibited a positive correlation with HSF4 mRNA expression. Unfortunately, the prognostic and diagnostic performance of these CpG loci in CRC patients was mediocre. In CRC, there were 1694 HSF4 methylation-related genes; 1468 of which displayed positive and 226 negative associations, and they were involved in regulating phenotypes such as immune, inflammatory, and metabolic reprogramming. EGFR, RELA, STAT3, FCGR3A, POLR2K, and AXIN1 are hub genes among the HSF4 methylation-related genes.

CONCLUSION

HSF4 is highly methylated in CRC, but there is no significant correlation between it and the prognosis and diagnosis of CRC. HSF4 methylation may serve as one of the ways in which HSF4 mediates the CRC process.

Keywords: Colorectal cancer; DNA methylation; Prognosis; Diagnosis; Bioinformatics; Heat shock factor protein 4

Core Tip: Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract with clinical manifestations of diarrhea, constipation, and abdominal pain. We previously demonstrated that heat shock factor protein 4 (HSF4) accelerates the malignant biological behavior of CRC cells in vivo and in vitro. This study reveals that HSF4 is highly methylated and associated with HSF4 overexpression in CRC. Although the diagnostic and prognostic value of HSF4 methylation is poor, it may be involved in the process of CRC by mediating the expression of HSF4 or related genes. Combined with the finding of our previous study, the present study suggests that the high expression of HSF4 mRNA and protein and its oncogenic effects are likely to be associated with HSF4 methylation.