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Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers

Ian MacFawn1, Hannah Wilson1, Luke A Selth2

  • 1West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States.

Molecular Immunology
|December 4, 2018
PubMed

Insights

Natural Killer (NK) cells are crucial for cancer suppression. This study reveals how the epithelial phenotype, regulated by Grainyhead-like-2 (GRHL2), enhances NK cell activity and killing through epigenetic mechanisms.

Area of Science:

  • Immunology
  • Cancer Biology
  • Epigenetics

Background:

  • Natural Killer (NK) cells are vital in suppressing tumor initiation and metastasis.
  • Carcinomas exhibit heterogeneity, with epithelial, mesenchymal, and hybrid tumor cells, impacting NK cell susceptibility.
  • Grainyhead-like-2 (GRHL2) is a key regulator of the epithelial phenotype, downregulated during Epithelial-Mesenchymal Transition (EMT).

Purpose of the Study:

  • To elucidate the molecular mechanisms linking the epithelial phenotype to NK cell sensitivity.
  • To investigate the role of GRHL2 in modulating NK cell interactions with tumor cells.
  • To identify novel epigenetic pathways connecting epithelial characteristics with NK cell-mediated killing.

Main Methods:

  • Re-expression of GRHL2 in tumor cells to study its effects on NK susceptibility.
  • Analysis of ICAM-1 and interferon response gene expression.
  • Identification of GRHL2-interacting proteins using proteomic approaches.
  • Investigation of epigenetic modifications involving KMT2C, KMT2D, and p300.

Main Results:

  • GRHL2 re-expression increased ICAM-1 expression, enhancing NK cell-target cell interactions and NK cell-mediated killing.
  • Expression of interferon response genes, including ICAM1, inversely correlated with EMT.
  • Two novel GRHL2-interacting proteins, KMT2C and KMT2D (histone methyltransferases), were identified.
  • GRHL2-KMT2C/D interactions and GRHL2's inhibition of p300 promoted mesenchymal-epithelial transition, NK sensitization, and ICAM-1 expression.

Conclusions:

  • GRHL2 plays a critical role in sensitizing epithelial tumor cells to NK cell-mediated killing.
  • Novel epigenetic mechanisms involving KMT2C, KMT2D, and p300 connect the epithelial phenotype to NK cell susceptibility.
  • These findings reveal potentially targetable pathways for enhancing cancer immunotherapy.
Keywords:
EpigeneticGrainyhead-like-2ICAM-1KMT2CKMT2DMesenchymal-to-epithelial transitionNK cellsp300

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