Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma
Shigeki Sekine, … , Naoya Yamazaki, Taisuke Mori
Shigeki Sekine, … , Naoya Yamazaki, Taisuke Mori
Published May 30, 2019
Citation Information: J Clin Invest. 2019;129(9):3827-3832. https://doi.org/10.1172/JCI126185.
View: Text | PDF
Concise Communication Dermatology Oncology

Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma

  • Text
  • PDF
Abstract

Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescence in situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.

Authors

Shigeki Sekine, Tohru Kiyono, Eijitsu Ryo, Reiko Ogawa, Susumu Wakai, Hitoshi Ichikawa, Koyu Suzuki, Satoru Arai, Koji Tsuta, Mitsuaki Ishida, Yuko Sasajima, Naoki Goshima, Naoya Yamazaki, Taisuke Mori

×

Figure 4

Functional significance of YAP1 and WWTR1 fusions.

Options: View larger image (or click on image) Download as PowerPoint
Functional significance of YAP1 and WWTR1 fusions.
(A) Structures of the...
(A) Structures of the putative fusion gene products expressed in poromas and porocarcinomas. Arrows indicate fusion breakpoints. Notice that YAP1-MAML2, YAP1-NUTM1, and WWTR1-NUTM1 fusion gene products harbor a TEAD-binding domain derived from YAP1 or WWTR1 and a p300-binding domain derived from MAML2 or NUTM1. (B)Intracellular localization of YAP1 fusion gene products. The FLAG-tagged proteins were detected by immunofluorescence staining with nuclear staining using DAPI. Scale bars: 10 μm. (C) TEAD luciferase reporter assays on HEK293T cells transfected with doxycycline-inducible vectors. YAP1S127A and YAP15SA represent constitutively active mutants. The luciferase activity of EGFP-transfected cells in the absence of doxycycline was set at 1 to indicate relative luciferase activities. Data represent mean of triplicate measurements ± SD. (D) Soft agar colony formation assay of NIH3T3 cells expressing the fusion transgenes. NIH3T3 cells were transduced with doxycycline-inducible retrovirus vectors to express the respective transgenes and subjected to a soft agar colony formation assay in the presence of doxycycline. None of the clones formed colonies in the absence of doxycycline. Scale bar: 200 μm.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts