TY - JOUR
T1 - PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma
AU - Vidarsdottir, Linda
AU - Azimi, Alireza
AU - Das, Ishani
AU - Sigvaldadottir, Ingibjorg
AU - Suryo Rahmanto, Aldwin
AU - Petri, Andreas
AU - Kauppinen, Sakari
AU - Ingvar, Christian
AU - Jönsson, Göran
AU - Olsson, Håkan
AU - Frostvik Stolt, Marianne
AU - Tuominen, Rainer
AU - Sangfelt, Olle
AU - Pokrovskaja Tamm, Katja
AU - Hansson, Johan
AU - Grandér, Dan
AU - Egyházi Brage, Suzanne
AU - Johnsson, Per
PY - 2021/5/26
Y1 - 2021/5/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106901248&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-89389-9
DO - 10.1038/s41598-021-89389-9
M3 - Journal article
C2 - 34040017
SN - 2045-2322
VL - 11
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11023
ER -