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Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73

Masahiro Kawahara1, Toshiyuki Hori, Kazuhisa Chonabayashi

  • 1Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Blood
|June 21, 2008
PubMed

Insights

The Kpm/Lats2 tumor suppressor is crucial for leukemia chemotherapy sensitivity. Its down-regulation increases resistance by impairing p73 target gene induction, impacting DNA damage response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Kpm/Lats2 tumor suppressor is downregulated in malignancies, correlating with poor prognosis in acute lymphoblastic leukemia.
  • Kpm/Lats2 is decreased in chemotherapy-resistant leukemias.

Purpose of the Study:

  • To investigate the role of Kpm/Lats2 in leukemia chemoresistance.
  • To elucidate the mechanism by which Kpm/Lats2 influences the DNA damage response and chemosensitivity.

Main Methods:

  • Kpm/Lats2 expression was silenced in leukemic cells.
  • Cells were treated with DNA damage-inducing agents.
  • Expression of p21, PUMA, and p73 was analyzed.
  • Chromatin immunoprecipitation (ChIP) assays were performed.
  • Transient coexpression analyses were conducted.

Main Results:

  • Kpm/Lats2 silencing increased chemoresistance without affecting cell growth.
  • DNA damage-induced p21 and PUMA expression was impaired in Kpm/Lats2-knockdown cells.
  • Nuclear accumulation and PUMA promoter recruitment of p73 were reduced upon Kpm/Lats2 knockdown.
  • Kpm/Lats2 stabilizes YAP2 and p73, dependent on its kinase activity and YAP2 phosphorylation.

Conclusions:

  • Kpm/Lats2 is involved in regulating p73 stability and function.
  • Kpm/Lats2 promotes chemosensitivity in leukemic cells by inducing p73 target genes via YAP2 phosphorylation.
  • Kpm/Lats2 represents a potential therapeutic target for overcoming chemoresistance in leukemia.

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