J Cancer 2020; 11(10):2874-2886. doi:10.7150/jca.38815

Research Paper

Promoter Hypermethylation of CHODL Contributes to Carcinogenesis and Indicates Poor Survival in Patients with Early-stage Colorectal Cancer

Xinyue Zhang1,2*, Kaiming Wu3*, Yuhua Huang4, Lixia Xu1, Xiaoxing Li2✉, Ning Zhang1✉

1. Department Of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 510080
2. Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 510080
3. Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 510080
4. Department Of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China, 510080
* These authors contributed equally to this study.

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Citation:
Zhang X, Wu K, Huang Y, Xu L, Li X, Zhang N. Promoter Hypermethylation of CHODL Contributes to Carcinogenesis and Indicates Poor Survival in Patients with Early-stage Colorectal Cancer. J Cancer 2020; 11(10):2874-2886. doi:10.7150/jca.38815. Available from http://www.jcancer.org/v11p2874.htm

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Abstract

Aims: Aberrant hypermethylation of CpG islands is an important hallmark of colorectal cancer (CRC). We previously utilized methyl-DNA immunoprecipitation assays to identify a novel methylated gene, chondrolectin (CHODL), preferentially methylated in human CRC. In this study, we examined the epigenetic inactivation, biological effects and prognostic significance of CHODL in CRC.

Main methods: The methylation status of CHODL in CRC was evaluated by bisulfite genomic sequencing (BGS). The functions of CHODL in CRC were determined by proliferation, apoptosis, cell migration and invasion assays. The impact and underlying mechanisms of CHODL in CRC were characterized by western blot and RNA-Seq analyses. The association between CHODL and CRC clinical features was examined using The Cancer Genome Atlas (TCGA) database and immunohistochemical staining.

Key findings: CHODL was downregulated in 10 CRC cell lines and CRC tissues, and promoter hypermethylation contributed to its inactivation. Ectopic expression of CHODL inhibited colony formation, suppressed cell viability, induced apoptosis, and restrained cell migration and invasion in vitro and in vivo. Furthermore, high CHODL expression in CRC was a predictor of improved survival, though CHODL hypermethylation was a poor prognostic factor for CRC patients, especially those with early-stage CRC.

Significance: CHODL promoter hypermethylation silences CHODL expression in CRC, and CHODL suppresses CRC tumorigenesis. CHODL methylation and expression levels can be used as potential markers to evaluate the prognosis of CRC patients.

Keywords: CHODL, methylation, prognosis, carcinogenesis, colorectal cancer