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PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

Vidarsdottir, Linda ; Azimi, Alireza ; Das, Ishani ; Sigvaldadottir, Ingibjorg ; Suryo Rahmanto, Aldwin ; Petri, Andreas ; Kauppinen, Sakari ; Ingvar, Christian LU ; Jönsson, Göran LU and Olsson, Håkan LU orcid , et al. (2021) In Scientific Reports 11(1).
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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
11023
publisher
Nature Publishing Group
external identifiers
  • scopus:85106901248
  • pmid:34040017
ISSN
2045-2322
DOI
10.1038/s41598-021-89389-9
language
English
LU publication?
yes
id
cc2891a1-64ca-48f9-ab3c-e64d55e29878
date added to LUP
2021-06-18 10:03:08
date last changed
2024-06-15 12:45:45
@article{cc2891a1-64ca-48f9-ab3c-e64d55e29878,
  abstract     = {{<p>BRAF inhibitors (BRAFi) selectively target oncogenic BRAF<sup>V600E/K</sup> 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.</p>}},
  author       = {{Vidarsdottir, Linda and Azimi, Alireza and Das, Ishani and Sigvaldadottir, Ingibjorg and Suryo Rahmanto, Aldwin and Petri, Andreas and Kauppinen, Sakari and Ingvar, Christian and Jönsson, Göran and Olsson, Håkan and Frostvik Stolt, Marianne and Tuominen, Rainer and Sangfelt, Olle and Pokrovskaja Tamm, Katja and Hansson, Johan and Grandér, Dan and Egyházi Brage, Suzanne and Johnsson, Per}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-89389-9}},
  doi          = {{10.1038/s41598-021-89389-9}},
  volume       = {{11}},
  year         = {{2021}},
}