All-trans-retinoic acid antagonizes the hedgehog pathway by inducing patched

Alexander M. Busch, Fabrizio Galimberti, Kristen E. Nehls, Monic Roengvoraphoj, David Sekula, Bin Li, Yongli Guo, James DiRenzo, Steven N. Fiering, Michael J. Spinella, David J. Robbins, Vincent A. Memoli, Sarah J. Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Male germ cell tumors (GCTs) are a model for a curable solid tumor. GCTs can differentiate into mature teratomas. Embryonal carcinomas (ECs) represent the stem cell compartment of GCTs and are the malignant counterpart to embryonic stem (ES) cells. GCTs and EC cells are useful to investigate differentiation therapy and chemotherapy response. This study explored mechanistic interactions between all-trans-retinoic acid (RA), which induces differentiation of EC and ES cells, and the Hedgehog (Hh) pathway, a regulator of self-renewal and proliferation. RA was found to induce mRNA and protein expression of Patched 1 (Ptch1), the Hh ligand receptor and negative regulator of this pathway. PTCH1 is also a target gene of Hh signaling through Smoothened (Smo) activation. Yet, this observed RA-mediated Ptch1 induction was independent of Smo. It occurred despite co-treatment with RA and Smo inhibitors. Retinoid induction of Ptch1 also occurred in other RA-responsive cancer cell lines and in normal ES cells. Notably, this enhanced Ptch1 expression was preceded by induction of the homeobox transcription factor Meis1, a direct RA target. Direct interaction between Meis1 and Ptch1 was confirmed using chromatin immunoprecipitation assays. To establish the translational relevance of this work, Ptch1 expression was shown to be deregulated in human ECs relative to mature teratoma and the normal seminiferous tubule. Taken together, these findings reveal a previously unrecognized mechanism through which RA can inhibit the Hh pathway via Ptch1 induction. Engaging this pathway is a new way to repress the Hh pathway that can be translated into the cancer clinic.

Original languageEnglish (US)
Pages (from-to)463-472
Number of pages10
JournalCancer Biology and Therapy
Volume15
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • All-trans-retinoic acid
  • Differentiation
  • Embryonal carcinoma
  • Hedgehog
  • Ptch1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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