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Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms

S T Martin1, N Sato, S Dhara

  • 1Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Cancer Biology & Therapy
|June 23, 2005
PubMed

Insights

Human Hedgehog interacting protein (HHIP) is silenced by promoter methylation in pancreatic cancer, contributing to aberrant hedgehog signaling. Epigenetic drugs can restore HHIP expression, offering potential therapeutic strategies for pancreatic neoplasms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Aberrant hedgehog signaling is a hallmark of various human cancers.
  • Human Hedgehog interacting protein (HHIP) negatively regulates hedgehog signaling and is underexpressed in pancreatic cancers.

Purpose of the Study:

  • To investigate genetic and epigenetic alterations of the HHIP gene in pancreatic cancer.
  • To determine the role of HHIP inactivation in pancreatic cancer pathogenesis.

Main Methods:

  • Analysis of HHIP gene mutations and promoter CpG island methylation in pancreatic cancer cell lines, primary tumors, and xenografts.
  • Assessment of HHIP expression using real-time RT-PCR.
  • Treatment of cell lines with epigenetic modifier drugs to restore HHIP expression.
  • Evaluation of hedgehog signaling activity via Gli reporter assays.

Main Results:

  • No mutations in the HHIP gene were found.
  • Complete or partial promoter methylation of HHIP was detected in a significant proportion of pancreatic cancer cell lines (80%), primary cancers (46%), and xenografts (78%), but not in normal pancreata.
  • Methylation correlated with reduced or absent HHIP expression.
  • Epigenetic drug treatment restored HHIP expression and decreased hedgehog signaling activity.

Conclusions:

  • Epigenetic inactivation of HHIP via promoter methylation is a mechanism contributing to hedgehog pathway overactivity in pancreatic adenocarcinomas.
  • Restoration of HHIP expression by epigenetic therapy may represent a therapeutic approach for pancreatic cancer.

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