Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF‐β signalling

Abstract

Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 in GC, eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non-tumour tissues were examined. Methylation-specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH1 expression correlated with promoter region methylation in GC cells, and re-expression was induced by 5-Aza-2′-deoxyazacytidine. DACH1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non-tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 expression inhibited epithelial–mesenchymal transition and metastasis by inhibiting transforming growth factor (TGF)-β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1-expressed BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF-β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.

DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

“…As to the clinical-pathological relevance of DACH1 in NSCLC, we observed that DACH1 abundance was inversely corelated with tumor stage, grade and metastasis, which is consistent with previous reports [10,12-14,23]. Thus far, only a handful of reports have explored the value of DACH1 as a molecular marker for cancer prognosis.…”

“…Recent findings supported the role of DACH1 as a novel tumor suppresor in several kinds of human cancers [5,12-25]. The link of DACH1 to lung cancer was initially uncovered by whole-genome and transcriptome sequencing of NSCLC samples.…”

“…Recently, more evidence indicates RDGN network is implicated in the development of human cancer, including breast and lung carcinoma [5-10]. Functional studies have identified DACH1 as a negative regulator of TGF-β and Wnt signaling to repress cancer cell migration and invasion [11,12]. DACH1 inhibits cell cycle progression and oncogenic transformation, as well as blocks paracrine signaling [13-15].…”

The retinal determination gene network: from developmental regulator to cancer therapeutic target

“…Subsequently, DACH1 was found to restrain TGF-β/SMAD-induced EMT [50]. DACH1 may also antagonize EMT in part by inactivating Wnt/β-catenin signaling; indeed, DACH1 was recently found to downregulate β-catenin in hepatocellular and gastric cancer [35, 51].…”

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers

“…For example, expression of DACH1 inhibited epithelial-mesenchymal transition and metastasis by inhibiting TGF-β-induced signaling. 65 Tumor size was reduced in xenografted mice with DACH1-expressing BGC823 cells. TGF-β-induced epithelial-mesenchymal transition was also noted in ovarian cancer HEYC2 cells, by increasing both expression and activity of DNMT1, DNMT3A, and DNMT3B.…”