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Downregulation of HP1? suppresses proliferation of cholangiocarcinoma by restoring SFRP1 expression.

ABSTRACT: Heterochromatin protein 1? (HP1?) is a gene that mediates chromatin conformation, gene silencing and cancer progression. However, little is known regarding the impact of HP1? in the pathogenesis of cholangiocarcinoma (CCA). In the present study, we demonstrate that HP1? is significantly upregulated in CCA tissues and cell lines, while downregulation of HP1? leads to suppression of cell proliferation. Then we find that downregulation of HP1? can decrease H3K9me3 enrichment and DNA methylation rate of secreted frizzled-related protein 1 (SFRP1) promoter, resulting in restoring the expression of SFRP1. Moreover, restoration of SFRP1 expression can suppress CCA cells proliferation. These results provide a mechanistic understanding of the role of HP1? in the pathogenesis of CCA and may offer a novel therapeutic target in this disease.

SUBMITTER: Cheng W

PROVIDER: S-EPMC5217004 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Downregulation of HP1α suppresses proliferation of cholangiocarcinoma by restoring SFRP1 expression.

Cheng Wenlong W Tian Li L Wang Bing B Qi Yongqiang Y Huang Wenhua W Li Hongbo H Chen Yong-Jun YJ

Oncotarget 20160701 30

Heterochromatin protein 1α (HP1α) is a gene that mediates chromatin conformation, gene silencing and cancer progression. However, little is known regarding the impact of HP1α in the pathogenesis of cholangiocarcinoma (CCA). In the present study, we demonstrate that HP1α is significantly upregulated in CCA tissues and cell lines, while downregulation of HP1α leads to suppression of cell proliferation. Then we find that downregulation of HP1α can decrease H3K9me3 enrichment and DNA methylation rat ...[more]

PMID: 27385214

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Project description:ObjectiveThe tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME.MethodsWe constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages.ResultsOur findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages.ConclusionsDPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.

Dataset Information

Downregulation of HP1? suppresses proliferation of cholangiocarcinoma by restoring SFRP1 expression.

Publications

Downregulation of HP1α suppresses proliferation of cholangiocarcinoma by restoring SFRP1 expression.

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