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The signalling axis ERK5/KLF2 is a major determinant of chemical sarcomagenesis

ABSTRACT: Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this particular MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth, colony-forming capacity, and caused a marked loss of tumor growth in vivo. Indeed, the transcriptomic profile in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration or motility, among others. Finally, among the various differentially expressed genes, Klf2, a direct target of the ERK5 pathway, is a key mediator of the biological effects of ERK5 in vitro and in vivo, as indicated by its specific interference. Therefore, our data suggest that the ERK5KLF2 signaling axis is an important determinant of 3MC-induced sarcomas and should be further studied in human sarcomas, especially those of muscular origin.

ORGANISM(S): Mus musculus

PROVIDER: GSE199395 | GEO | 2022/08/03

REPOSITORIES: GEO

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Project description:In skeletal muscle differentiation, muscle-specific genes are regulated by two groups of transcription factors, the MyoD and MEF2 families, which work together to drive the differentiation process. Here we show that ERK5 regulates muscle cell fusion through Klf transcription factors. The inhibition of ERK5 activity suppresses muscle cell fusion with minimal effects on the expression of MyoD, MEF2, and their target genes. Promoter analysis coupled to microarray assay reveals that Klf-binding motifs are highly enriched in the promoter regions of ERK5-dependent upregulated genes. Remarkably, Klf2 and Klf4 expression are also upregulated during differentiation in an ERK5-dependent manner, and knockdown of Klf2 or Klf4 specifically suppresses muscle cell fusion. Moreover, we show that the Sp1 transcription factor links ERK5 to Klf2/4, and that nephronectin, a Klf transcriptional target, is involved in muscle cell fusion. Therefore, an ERK5/Sp1/Klf module plays a key role in the fusion process during skeletal muscle differentiation. To identify those genes whose expression levels are regulated by the ERK5 pathway in differentiating C2C12 cells, we performed genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays. We performed two independent experiments. For each experiment, we used five samples: cells in growth medium (0 day), lacZ-infected cells at two time points (2.5 days and 4.5 days of differentiation) and dnMEK5-infected cells at two time points (2.5 days and 4.5 days of differentiation). Each virus was infected at 1 day of differentiation. Total RNA was prepared using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions. The total RNA of each condition was obtained from two independent experiments. Synthesis of cDNA in vitro transcription and biotin labeling cRNA, and hybridization to the Mouse Genome 430 2.0 array (Affymetrix) were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned Chip images were analyzed with GeneChip operating Software v.1.4 (GCOS) and GeneSpring GX 11.0.2. (Agilent technologies).

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The signalling axis ERK5/KLF2 is a major determinant of chemical sarcomagenesis

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