Dataset Information

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT₁ receptor to promote lung adenocarcinoma growth.

ABSTRACT:

Introduction

The human genome encodes two melatonin receptors (MT₁ and MT₂) that relay melatonin signals to cellular interior. Accumulating evidence has linked melatonin to multiple health benefits, among which its anticancer effects have become well-established. However, the implications of its receptors in lung adenocarcinoma have so far remained incompletely understood.

Objectives

This study aims to investigate the response of the MT₁ receptor to melatonin treatment and its dynamic regulation by ubiquitin-specific protease 8 (USP8) in lung adenocarcinoma.

Methods

The mRNA levels of MT₁ and MT₂ receptors were analyzed with sequencing data. The expression and localization of the MT₁ receptor with melatonin treatment were investigated by immunoblotting, immunofluorescence and confocal microscopy assays. Endocytic deubiquitylases were screened to identify MT₁ association. The effects of USP8 were assessed with shRNA-mediated knockdown and small molecule inhibitor. The combined efficacy of melatonin and USP8 suppression was also evaluated using xenograft animal models.

Results

Bioinformatic analysis revealed increased expression of the MT₁ receptor in lung adenocarcinoma tissues. Melatonin treatment leads to the downregulation of the MT₁ receptor in lung adenocarcinoma cells, which is attributed to receptor endocytosis and lysosomal degradation via the canonical endo-lysosomal route. USP8 negatively regulates the endocytic degradation of the MT₁ receptor incurred by melatonin exposure and thus protects lung adenocarcinoma cell growth. USP8 suppression by knockdown or pharmacological inhibition effectively deters cancer cell proliferation and sensitizes lung adenocarcinoma cells to melatonin in vitro. Furthermore, USP8 silencing significantly potentiates the anticancer effects of melatonin in xenograft tumor models.

Conclusion

The MT₁ receptor responds to melatonin treatment and is endocytosed for lysosomal degradation that is counteracted by USP8. The inhibition of USP8 demonstrates tumor-suppressive effects and thus can be exploited as potential therapeutic strategy either as monotherapy or combined therapy with melatonin.

SUBMITTER: Sun Q

PROVIDER: S-EPMC9637587 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT<sub>1</sub> receptor to promote lung adenocarcinoma growth.

Sun Qianhui Q Zhang Jinrui J Li Xiaoxi X Yang Guoheng G Cheng Shaoxuan S Guo Dong D Zhang Qingqing Q Sun Feng F Zhao Feng F Yang Dian D Wang Shanshan S Wang Taishu T Liu Shuyan S Zou Lijuan L Zhang Yingqiu Y Liu Han H

Journal of advanced research 20220201

<h4>Introduction</h4>The human genome encodes two melatonin receptors (MT<sub>1</sub> and MT<sub>2</sub>) that relay melatonin signals to cellular interior. Accumulating evidence has linked melatonin to multiple health benefits, among which its anticancer effects have become well-established. However, the implications of its receptors in lung adenocarcinoma have so far remained incompletely understood.<h4>Objectives</h4>This study aims to investigate the response of the MT<sub>1</sub> receptor t ...[more]

PMID: 36328739

Similar Datasets

Project description:Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2)3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

Dataset Information

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT₁ receptor to promote lung adenocarcinoma growth.

Introduction

Objectives

Methods

Results

Conclusion

Publications

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT<sub>1</sub> receptor to promote lung adenocarcinoma growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT1 receptor to promote lung adenocarcinoma growth.

Introduction

Objectives

Methods

Results

Conclusion

Publications

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT<sub>1</sub> receptor to promote lung adenocarcinoma growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The ubiquitin-specific protease 8 antagonizes melatonin-induced endocytic degradation of MT₁ receptor to promote lung adenocarcinoma growth.