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

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.