PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma
Abstract BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecula...
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2021
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oai:doaj.org-article:f88ae22862f24b9684552bdca23e8edf2021-12-02T15:00:55ZPTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma10.1038/s41598-021-89389-92045-2322https://doaj.org/article/f88ae22862f24b9684552bdca23e8edf2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89389-9https://doaj.org/toc/2045-2322Abstract BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.Linda VidarsdottirAlireza AzimiIshani DasIngibjorg SigvaldadottirAldwin Suryo RahmantoAndreas PetriSakari KauppinenChristian IngvarGöran JönssonHåkan OlssonMarianne Frostvik StoltRainer TuominenOlle SangfeltKatja Pokrovskaja TammJohan HanssonDan GrandérSuzanne Egyházi BragePer JohnssonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
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Medicine R Science Q Linda Vidarsdottir Alireza Azimi Ishani Das Ingibjorg Sigvaldadottir Aldwin Suryo Rahmanto Andreas Petri Sakari Kauppinen Christian Ingvar Göran Jönsson Håkan Olsson Marianne Frostvik Stolt Rainer Tuominen Olle Sangfelt Katja Pokrovskaja Tamm Johan Hansson Dan Grandér Suzanne Egyházi Brage Per Johnsson PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| description |
Abstract BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma. |
| format |
article |
| author |
Linda Vidarsdottir Alireza Azimi Ishani Das Ingibjorg Sigvaldadottir Aldwin Suryo Rahmanto Andreas Petri Sakari Kauppinen Christian Ingvar Göran Jönsson Håkan Olsson Marianne Frostvik Stolt Rainer Tuominen Olle Sangfelt Katja Pokrovskaja Tamm Johan Hansson Dan Grandér Suzanne Egyházi Brage Per Johnsson |
| author_facet |
Linda Vidarsdottir Alireza Azimi Ishani Das Ingibjorg Sigvaldadottir Aldwin Suryo Rahmanto Andreas Petri Sakari Kauppinen Christian Ingvar Göran Jönsson Håkan Olsson Marianne Frostvik Stolt Rainer Tuominen Olle Sangfelt Katja Pokrovskaja Tamm Johan Hansson Dan Grandér Suzanne Egyházi Brage Per Johnsson |
| author_sort |
Linda Vidarsdottir |
| title |
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| title_short |
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| title_full |
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| title_fullStr |
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| title_full_unstemmed |
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma |
| title_sort |
ptenp1-as contributes to braf inhibitor resistance and is associated with adverse clinical outcome in stage iii melanoma |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/f88ae22862f24b9684552bdca23e8edf |
| work_keys_str_mv |
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