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Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17-92 cluster

Y Yan1, E A Hanse2,3, K Stedman2,4

  • 1Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Cell Death and Differentiation
|February 13, 2016
PubMed

Insights

PHLPP2 protein is suppressed in acute myeloid leukemia (AML) by miR-17-92. All-trans-retinoic acid (ATRA) upregulates PHLPP2 by inhibiting miR-17-92 via C/EBPβ, revealing a novel therapeutic mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PHLPP2, a tumor suppressor in solid tumors, has poorly understood regulation in hematological malignancies.
  • PHLPP2 protein, but not mRNA, is suppressed in late-stage acute myeloid leukemia (AML).

Purpose of the Study:

  • Investigate PHLPP2 regulation in AML.
  • Identify mechanisms controlling PHLPP2 expression and activity in myeloid differentiation.

Main Methods:

  • Analysis of PHLPP2 protein and mRNA expression in AML subtypes.
  • Investigated the role of miR-17-92 cluster in PHLPP2 regulation.
  • Assessed the effect of all-trans-retinoic acid (ATRA) on miR-17-92 and PHLPP2.
  • Determined the role of transcription factor C/EBPβ in mediating ATRA's effect.

Main Results:

  • miR-17-92 cluster directly inhibits PHLPP2 protein expression.
  • High miR-17-92 expression correlates with low PHLPP2 protein in AML cells.
  • ATRA suppresses miR-17-92, increasing PHLPP2 protein and activity.
  • C/EBPβ mediates ATRA's repression of the miR-17-92 gene promoter.

Conclusions:

  • A novel mechanism for PHLPP2 upregulation involves C/EBPβ-mediated repression of the miR-17-92 cluster.
  • This pathway is crucial in terminally differentiating myeloid cells, offering therapeutic potential for AML.

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