Frontiers in Cell and Developmental Biology (Feb 2022)
Histone 3 Methyltransferases Alter Melanoma Initiation and Progression Through Discrete Mechanisms
- Sara E. DiNapoli,
- Sara E. DiNapoli,
- Raúl Martinez-McFaline,
- Raúl Martinez-McFaline,
- Hao Shen,
- Hao Shen,
- Ashley S. Doane,
- Alexendar R. Perez,
- Akanksha Verma,
- Amanda Simon,
- Isabel Nelson,
- Isabel Nelson,
- Courtney A. Balgobin,
- Courtney A. Balgobin,
- Caitlin T. Bourque,
- Caitlin T. Bourque,
- Jun Yao,
- Jun Yao,
- Renuka Raman,
- Renuka Raman,
- Wendy Béguelin,
- Wendy Béguelin,
- Jonathan H. Zippin,
- Olivier Elemento,
- Ari M. Melnick,
- Ari M. Melnick,
- Yariv Houvras,
- Yariv Houvras,
- Yariv Houvras
Affiliations
- Sara E. DiNapoli
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Sara E. DiNapoli
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Raúl Martinez-McFaline
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Raúl Martinez-McFaline
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Hao Shen
- Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, United States
- Hao Shen
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
- Ashley S. Doane
- Caryl and Israel Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, United States
- Alexendar R. Perez
- Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, United States
- Akanksha Verma
- Caryl and Israel Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, United States
- Amanda Simon
- Department of Dermatology, Weill Cornell Medicine, New York, NY, United States
- Isabel Nelson
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Isabel Nelson
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Courtney A. Balgobin
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Courtney A. Balgobin
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Caitlin T. Bourque
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Caitlin T. Bourque
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Jun Yao
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Jun Yao
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Renuka Raman
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Renuka Raman
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Wendy Béguelin
- Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, United States
- Wendy Béguelin
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
- Jonathan H. Zippin
- Department of Dermatology, Weill Cornell Medicine, New York, NY, United States
- Olivier Elemento
- Caryl and Israel Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, United States
- Ari M. Melnick
- Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, United States
- Ari M. Melnick
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
- Yariv Houvras
- Department of Surgery, Weill Cornell Medicine, New York, NY, United States
- Yariv Houvras
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
- Yariv Houvras
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
- DOI
- https://doi.org/10.3389/fcell.2022.814216
- Journal volume & issue
-
Vol. 10
Abstract
Perturbations to the epigenome are known drivers of tumorigenesis. In melanoma, alterations in histone methyltransferases that catalyze methylation at histone 3 lysine 9 and histone 3 lysine 27—two sites of critical post-translational modification—have been reported. To study the function of these methyltransferases in melanoma, we engineered melanocytes to express histone 3 lysine-to-methionine mutations at lysine 9 and lysine 27, which are known to inhibit the activity of histone methyltransferases, in a zebrafish melanoma model. Using this system, we found that loss of histone 3 lysine 9 methylation dramatically suppressed melanoma formation and that inhibition of histone 3 lysine 9 methyltransferases in human melanoma cells increased innate immune response signatures. In contrast, loss of histone 3 lysine 27 methylation significantly accelerated melanoma formation. We identified FOXD1 as a top target of PRC2 that is silenced in melanocytes and found that aberrant overexpression of FOXD1 accelerated melanoma onset. Collectively, these data demonstrate how histone 3 lysine-to-methionine mutations can be used to uncover critical roles for methyltransferases.
Keywords