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P62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [UACC62_6days]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99832 | GEO | 2018/07/05

REPOSITORIES: GEO

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Project description:Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. Gene expression profiles were analyzed to examine the effects of p62 depletion in mouse with or without mutant huntingtin exon 1 To examine the effect of p62 depletion on the transcriptome of Huntington's disease model mice, we crossed p62 knockout mice with HD model mice. We extracted total RNA from the striatum of these mice at 8 weeks and used for a microaaray analysis. The samples are HD transgenic mice with p62 knockout (HD_p62KO), HD mice with normal p62 (HD_p62WT), non-HD-transgenic mice with p62 knockout (NT_p62KO), and non-HD-transgenic mice with normal p62 (NT_p62WT).

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P62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [UACC62_6days]

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