The Acetyltransferase KAT5 Inhibitor NU 9056 Promotes Apoptosis and Inhibits JAK2/STAT3 Pathway in Extranodal NK/T Cell Lymphoma

Anticancer Agents Med Chem. 2022;22(8):1530-1540. doi: 10.2174/1871520621666210908103306.

Abstract

Background: Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive malignant non- Hodgkin's lymphoma (NHL) with a poor prognosis. Therefore, novel therapeutic biomarkers and agents must be identified for the same. KAT5 inhibitor, NU 9056, is a small molecule that can inhibit cellular proliferation; however, its role in ENKTL has not been studied.

Objective: The present study investigated the effect of NU 9056 in ENKTL cells and explored the possible molecular mechanism for its antitumour effect.

Methods: The role of NU 9056 in ENKTL cells was investigated through the Cell Counting Kit-8 assay, flow cytometry, Western blot, and real-time quantitative polymerase chain reaction assay.

Results: NU 9056 inhibited ENKTL cell proliferation and induced G2/M phase arrest. NU 9056 also induced apoptosis by upregulating DR4, DR5, and caspase 8 expressions. Additionally, NU 9056 increased the expression of Bax, Bid, and cytochrome C and decreased the expression of Bcl-2, Mcl-1, and XIAP. Furthermore, NU 9056 activated endoplasmic reticulum (ER) stress and inhibited the JAK2/STAT3 signalling pathway. The p38 mitogen-activated protein kinase (MAPK) signalling pathway was also activated by NU 9056, and the ERK signalling pathway was suppressed in natural killer/T cell lymphoma cells.

Conclusion: NU 9056 inhibited cell proliferation, arrested cell cycle in the G2/M phase, and induced apoptosis through the stimulation of ER stress, thus inhibiting the JAK2/STAT3 signalling pathway and regulating MAPK pathways in ENKTL cells.

Keywords: ENKTL; JAK2/STAT3; KAT5; MAPK; NU 9056; apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism
  • Acetyltransferases / pharmacology
  • Acetyltransferases / therapeutic use
  • Apoptosis
  • Cell Proliferation
  • Humans
  • Janus Kinase 2 / metabolism
  • Lymphoma, Extranodal NK-T-Cell* / drug therapy
  • Lymphoma, Extranodal NK-T-Cell* / metabolism
  • Lymphoma, Extranodal NK-T-Cell* / pathology
  • Lysine Acetyltransferase 5 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • JAK2 protein, human
  • Janus Kinase 2