Abstract
Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor that arises from the nasopharynx.According to global cancer statistics, there were 129,079 new cases of nasopharyngeal carcinoma (NPC) worldwide in 2018, and 72,987 people died of this cancer [1]
We examined the effects of Ubiquitin C-terminal hydrolase L1 (UCHL1) on the ubiquitination of CTTN, and we found that overexpression of UCHL1 increased CTTN ubiquitination
We have previously reported that hypermethylation of the HOPX, RAB37, and SHISA3 genes might serve as molecular biomarkers to predict NPC metastasis [17,26,27]
Summary
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor that arises from the nasopharynx. According to global cancer statistics, there were 129,079 new cases of NPC worldwide in 2018, and 72,987 people died of this cancer [1]. The onset of intensity modulated radiotherapy and combined chemoradiotherapy has resulted in improved prognosis for patients with NPC, and the main cause of treatment failure of NPC is distant metastasis [2]. Efforts to better understanding the molecular mechanisms underlying NPC metastasis will help to get novel therapeutic strategies to improve treatment of metastatic NPC. UCHL1 is first reported to play an important role in the pathogenesis of Alzheimer’s disease [5]. UCHL1 has been reported to act as either an oncogene or tumor suppressor gene in
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