p62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [SKMEL_6days]

Metastasis is a common cancer hallmark which however, may be acquired by tumor-type specific mechanisms. Here we identify p62/SQSTM1 as a modulator of metastatic genes selectively enriched in melanoma. Loss- and gain-of-function analyses of p62 effectors revealed FERMT2 as an indicator of poor patient prognosis. Analyses in tumor cells, clinical biopsies and genetically-engineered mice (to compare p62 vs. ATG5) demonstrated that known p62 roles in autophagy and stress responses were not essential in melanomas. Instead, a genome-wide transcriptomic/proteomic/interactomic approach demonstrated that p62 controls FERMT2 and yet additional pro-metastatic genes by modulating transcript stability. This function of p62 was exerted by recruiting RNA-binding proteins, here exemplified by IGF2BP1. These data illustrate how genetically altered cancers can coordinately fuel pro-metastatic signatures. Two-condition experiment: shp62 vs. shControl. Biological replicates: 3 control replicates, 3 transfected replicates. 2 cell lines: SK-Mel-103, UACC62. 2 exposure times: 3 days, 6 days. This dataset includes cell line SK-Mel-103 at day 6.

转移是常见的癌症特征之一，但该特征可通过肿瘤类型特异性机制获得。本研究鉴定出p62/SQSTM1是选择性富集于黑色素瘤中的转移相关基因的调控因子。通过对p62效应分子的功能缺失与功能获得性分析，发现FERMT2可作为患者预后不良的标志物。在肿瘤细胞、临床活检组织以及基因工程小鼠（用于对比p62与ATG5）中开展的分析显示，p62在自噬与应激反应中的已知功能在黑色素瘤中并非必需。与之相反，全基因组转录组学、蛋白质组学及相互作用组学分析表明，p62可通过调控转录本稳定性，同时控制FERMT2及其他促转移基因的表达。p62的该功能通过招募RNA结合蛋白实现，本研究以IGF2BP1为例进行了展示。上述结果阐明了基因改变的癌症如何协同激活促转移基因特征。本实验设置两种处理条件：shp62组与shControl对照组。生物学重复：对照组与转染组各设3次重复。使用2种细胞系：SK-Mel-103与UACC62。设置2个处理时长：3天与6天。本数据集包含第6天时SK-Mel-103细胞系的相关数据。