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The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

Viviane Ponath1, Miriam Frech2, Mathis Bittermann1

  • 1Institute for Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Philipps University of Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany.

Cancers
|October 7, 2020
PubMed

Insights

Downregulating the SKI oncogene in pancreatic cancer enhances natural killer (NK) cell killing. SKI represses NKG2D ligand expression, suggesting a combination therapy for pancreatic tumors with high SKI levels.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Histone deacetylase inhibitors (HDACi) suppress tumor growth and enhance NK cell cytotoxicity by increasing NKG2D ligand (NKG2D-L) expression.
  • CBP and p300 are key acetylases for NKG2D-L expression.
  • The role of the oncogenic transcriptional repressor SKI in this process is unknown.

Purpose of the Study:

  • To investigate the role of SKI in regulating NKG2D-L expression and NK cell-mediated cytotoxicity in pancreatic cancer.
  • To determine if SKI impacts the efficacy of HDACi in enhancing anti-tumor immunity.

Main Methods:

  • siRNA-mediated downregulation of SKI in pancreatic cancer cell lines (Panc-1, Patu8988t).
  • Assessment of NK cell-mediated cytotoxicity against SKI-depleted or control cells.
  • Analysis of NKG2D-L expression following SKI manipulation and/or HDACi treatment (LBH589, VPA).

Main Results:

  • Downregulation of SKI increased pancreatic cancer cell killing by primary NK cells.
  • This enhanced cytotoxicity did not correlate with increased NKG2D-L expression.
  • HDACi treatment induced NKG2D-L and NK cell killing independently of SKI levels.
  • Genetic ablation of SKI significantly enhanced NKG2D-L induction by HDACi.

Conclusions:

  • SKI acts as a repressor of inducible NKG2D-L expression in pancreatic cancer cells.
  • Targeting SKI in combination with HDAC inhibitors may represent a novel therapeutic strategy for pancreatic cancer, particularly in patients with high SKI expression.
Keywords:
NK cell immunosurveillanceNKG2Dhiston (de)acetylationpancreatic tumor

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