Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to...

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Main Authors: Hyungsoo Kim, Dennie T. Frederick, Mitchell P. Levesque, Zachary A. Cooper, Yongmei Feng, Clemens Krepler, Laurence Brill, Yardena Samuels, Nicholas K. Hayward, Ally Perlina, Adriano Piris, Tongwu Zhang, Ruth Halaban, Meenhard M. Herlyn, Kevin M. Brown, Jennifer A. Wargo, Reinhard Dummer, Keith T. Flaherty, Ze’ev A. Ronai
Format: Article
Language:English
Published: Elsevier 2015-06-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124715004660
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spelling doaj-adafe221293748a28456eeb05b0f1a0b2020-11-24T22:03:23ZengElsevierCell Reports2211-12472015-06-011191458147310.1016/j.celrep.2015.04.049Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 DeregulationHyungsoo Kim0Dennie T. Frederick1Mitchell P. Levesque2Zachary A. Cooper3Yongmei Feng4Clemens Krepler5Laurence Brill6Yardena Samuels7Nicholas K. Hayward8Ally Perlina9Adriano Piris10Tongwu Zhang11Ruth Halaban12Meenhard M. Herlyn13Kevin M. Brown14Jennifer A. Wargo15Reinhard Dummer16Keith T. Flaherty17Ze’ev A. Ronai18Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USAMassachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USADepartment of Dermatology, University Hospital of Zürich and University of Zürich, 8091 Zürich, SwitzerlandDepartments of Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USACancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USAMelanoma Research Center, Wistar Institute, Philadelphia, PA 19104, USACancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USAWeizmann Institute, Rehovot 76100, IsraelQIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, AustraliaCancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USAMassachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USALaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USADepartment of Dermatology, Yale School of Medicine, New Haven, CT 06520, USAMelanoma Research Center, Wistar Institute, Philadelphia, PA 19104, USALaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USADepartments of Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Dermatology, University Hospital of Zürich and University of Zürich, 8091 Zürich, SwitzerlandMassachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USACancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USADespite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.http://www.sciencedirect.com/science/article/pii/S2211124715004660
collection DOAJ
language English
format Article
sources DOAJ
author Hyungsoo Kim
Dennie T. Frederick
Mitchell P. Levesque
Zachary A. Cooper
Yongmei Feng
Clemens Krepler
Laurence Brill
Yardena Samuels
Nicholas K. Hayward
Ally Perlina
Adriano Piris
Tongwu Zhang
Ruth Halaban
Meenhard M. Herlyn
Kevin M. Brown
Jennifer A. Wargo
Reinhard Dummer
Keith T. Flaherty
Ze’ev A. Ronai
spellingShingle Hyungsoo Kim
Dennie T. Frederick
Mitchell P. Levesque
Zachary A. Cooper
Yongmei Feng
Clemens Krepler
Laurence Brill
Yardena Samuels
Nicholas K. Hayward
Ally Perlina
Adriano Piris
Tongwu Zhang
Ruth Halaban
Meenhard M. Herlyn
Kevin M. Brown
Jennifer A. Wargo
Reinhard Dummer
Keith T. Flaherty
Ze’ev A. Ronai
Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
Cell Reports
author_facet Hyungsoo Kim
Dennie T. Frederick
Mitchell P. Levesque
Zachary A. Cooper
Yongmei Feng
Clemens Krepler
Laurence Brill
Yardena Samuels
Nicholas K. Hayward
Ally Perlina
Adriano Piris
Tongwu Zhang
Ruth Halaban
Meenhard M. Herlyn
Kevin M. Brown
Jennifer A. Wargo
Reinhard Dummer
Keith T. Flaherty
Ze’ev A. Ronai
author_sort Hyungsoo Kim
title Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
title_short Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
title_full Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
title_fullStr Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
title_full_unstemmed Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
title_sort downregulation of the ubiquitin ligase rnf125 underlies resistance of melanoma cells to braf inhibitors via jak1 deregulation
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2015-06-01
description Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.
url http://www.sciencedirect.com/science/article/pii/S2211124715004660
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