Geometric regulation of histone state directs melanoma reprogramming

Junmin Lee, Thomas G. Molley, Christopher H. Seward, Amr A. Abdeen, Huimin Zhang, Xiaochun Wang, Hetvi Gandhi, Jia Lin Yang, Katharina Gaus, Kristopher A. Kilian

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Malignant melanoma displays a high degree of cellular plasticity during disease progression. Signals in the tumor microenvironment are believed to influence melanoma plasticity through changes in the epigenetic state to guide dynamic differentiation and de-differentiation. Here we uncover a relationship between geometric features at perimeter regions of melanoma aggregates, and reprogramming to a stem cell-like state through histone marks H3K4Me2 and H3K9Ac. Using an in vitro tumor microengineering approach, we find spatial enrichment of these histone modifications with concurrent expression of stemness markers. The epigenetic modifier PRDM14 overlaps with H3K9Ac and shows elevated expression in cells along regions of perimeter curvature. siRNA knockdown of PRDM14 abolishes the MIC phenotype suggesting a role in regulating melanoma heterogeneity. Our results suggest mechanotransduction at the periphery of melanoma aggregates may orchestrate the activity of epigenetic modifiers to regulate histone state, cellular plasticity, and tumorigenicity.

Original languageEnglish
Article number341
Number of pages9
JournalCommunications Biology
Volume3
Issue number1
DOIs
Publication statusPublished - 3 Jul 2020
Externally publishedYes

Keywords

  • biophysics
  • cancer
  • diseases
  • stem cells

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