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

DOI
https://doi.org/10.3389/fcell.2022.814216
Journal volume & issue
Vol. 10

Abstract

Read online

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