Abstract
BackgroundMost colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis. Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) with high expression in CRC tissues regulates CRC cell proliferation via Wnt/β-catenin pathway. We hypothesized that USP6NL impacts CRC growth and inhibition of USP6NL may be a novel treatment strategy to improve CRC therapy.MethodsUSP6NL level in human CRC tissues and its association with tumor growth and metastasis were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of CRC cells in vitro and in vivo.ResultsHerein, we found that USP6NL was up-regulated in tumorous tissues of CRC patients. Our data suggested that knockdown of USP6NL in human CRC cell lines (HCT116 and LOVO cells) inhibited cell proliferation, induced G0/G1 cell cycle arrest, and prevented the tumorigenicity of HCT116 cells in nude mice, and which was associated with the prevention of Wnt/β-catenin pathway. On the contrary, USP6NL overexpression in human CRC cells (SW480) showed the opposite result. Our data suggested that the promoted cell proliferation, G1/S cell cycle progression, and the enhanced expression of β-catenin Cyclin D1 and C-myc while reduced P27 induced by the overexpression of USP6NL were significantly reversed by additional treatment of XAV939, indicating that activating Wnt/β-catenin pathway was the mechanism, by which USP6NL exerted carcinogenesis in CRC in vitro. Besides, our data suggested that knockdown of USP6NL increased the ubiquitination of β-catenin, indicating that USP6NL may serve as a deubiquitinase that regulated β-catenin accumulation in this process. Furthermore, 10058-F4 down-regulated USP6NL, inhibited CRC cell proliferation and induced cell cycle arrest. The result demonstrated a possible feedback loop between USP6NL, β-catenin and C-myc in regulating CRC cell growth.ConclusionUSP6NL was an oncogene in CRC, and it may be a potential target for the treatment of CRC.
Highlights
Most colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis
Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) was enhanced in CRCTo investigate the involvement of USP6NL in human CRC, USP6NL expression in tumorous and none-tumorous colorectal tissue from CRC patients were detected
USP6NL mRNA expression data in CRC and corresponding healthy people were downloaded in The Cancer Genome Atlas database (TCGA) and GEO database
Summary
Most colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis. Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) with high expression in CRC tissues regu‐ lates CRC cell proliferation via Wnt/β-catenin pathway. GAP activity is essential for its oncogenic. Wnt/β-catenin signaling is essential in carcinogenesis, embryonic development and tissue homeostasis [7]. Activating Wnt signaling cascade contributes to the etiology of CRC during intestinal epithelium homeostasis and differentiation [8]. These primarily consist of recruitment of the transcription factor β-catenin in the nucleus and the stimulation many downstream oncogenes, for example c-Myc and Cyclin D-1 [7]. Increased expression of β-catenin has been consistently found in tumorous colon tissue, and predicts poor survival of CRC patients [9]. The mechanisms of the upregulation of β-catenin in CRC need to be fully understood
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