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PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells

ABSTRACT: TiO2-enriched and non-enriched samples and a pooled TiO2-enriched alkaline phosphatase treated sample from subconfluent A549 lung adenocarcinoma cells line. Cells were subjected to on of the 6 different treatments: Control sample, RNAi mediated depletion of PPP2R1A, CIP2A, or PME-1, and treatment with 100nM Trametinib for 20 hours for control and PPP2R1A depleted cells. Each condition was performed in triplicates with different siRNA sequences.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

SUBMITTER: Laxman Yetukuri

LAB HEAD: Jukka Westermarck (lab head) Laxman yetukuri (submitted)

PROVIDER: PXD009900 | Pride | 2018-10-11

REPOSITORIES: Pride

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Publications

PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells.

Kauko Otto O O'Connor Caitlin M CM Kulesskiy Evgeny E Sangodkar Jaya J Aakula Anna A Izadmehr Sudeh S Yetukuri Laxman L Yadav Bhagwan B Padzik Artur A Laajala Teemu Daniel TD Haapaniemi Pekka P Momeny Majid M Varila Taru T Ohlmeyer Michael M Aittokallio Tero T Wennerberg Krister K Narla Goutham G Westermarck Jukka J

Science translational medicine 20180701 450

Kinase inhibitor resistance constitutes a major unresolved clinical challenge in cancer. Furthermore, the role of serine/threonine phosphatase deregulation as a potential cause for resistance to kinase inhibitors has not been thoroughly addressed. We characterize protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. The results show that PP2A activity modulation alters cancer cell sensitivities to a l ...[more]

PMID: 30021885

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Project description:Methylation of cytosine in DNA (5mC) is an important epigenetic mark that is involved in the regulation of genome function. During early embryonic development in mammals, the DNA methylation landscape is dynamically reprogrammed in part through active demethylation. Recent advances have identified key players involved in active demethylation pathways, including oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) by the TET family of enzymes and excision of 5fC by the base excision repair enzyme thymine DNA glycosylase (TDG). Here, we provide the first genome-wide distribution map of 5fC in mouse embryonic stem (ES) cells and evaluate potential roles for 5fC in differentiation. Our method exploits the unique reactivity of 5fC to link a biotin tag for pulldown and high-throughput sequencing. Genome-wide mapping revealed 5fC enrichment in CpG islands (CGIs) of promoters and exons. CGI promoters in which 5fC was relatively more enriched than 5mC or 5hmC corresponded to transcriptionally active genes. Accordingly, 5fC-rich promoters had elevated H3K4me3 levels, a histone mark associated with active transcription, and were frequently bound by RNA Polymerase II. Downregulation of TDG led to accumulation of 5fC in CGIs in ES cells, which correlates with increased methylation in these genomic regions during differentiation and in mouse embryonic fibroblasts derived from TDG knockout embryos. Collectively, our data suggest that 5fC plays a role in epigenetic reprogramming. The formation and removal of this cytosine modification are confined to specific genomic regions, which are in part controlled by TDG. Notably, 5fC excision in ES cells is necessary for the correct establishment of CGI methylation patterns during differentiation, and hence, for appropriate patterns of gene expression during development. We devised a method to map 5-formylcytosine (5fC) by linking a biotin tag to 5fC for pulldown and high-throughput sequencing. We mapped 5fC in the following samples of mouse embryonic stem cells (J1): Wild-type ES cells (two replicates); ES cells transfected with siRNA targeting TDG (two replicates); ES cells transfected with non-targeting siRNA (two replicates). One genomic input library was also sequenced to detect and correct biases in fragment enrichment.

Dataset Information

PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells

Publications

PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells.

Similar Datasets

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