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

Y. Yan, E. A. Hanse, K. Stedman, J. M. Benson, X. H. Lowman, S. Subramanian, A. Kelekar

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein. Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells.

Original languageEnglish (US)
Pages (from-to)1232-1242
Number of pages11
JournalCell Death and Differentiation
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Funding Information:
This work was supported by NIH grant R01 CA157971 to AK and American Cancer Society grant RSG-13-381-01 to SS, NIHT32 (CA009138) training fellowships to EAH and JMB, F31 award (CA177119) to EAH, and a doctoral dissertation award to XHL.

Fingerprint Dive into the research topics of 'Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17-92 cluster in differentiating AML cells'. Together they form a unique fingerprint.

Cite this