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SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b

Sita Kugel1, Carlos Sebastián1, Julien Fitamant1

  • 1The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.

Cell
|May 17, 2016
PubMed

Insights

Sirtuin 6 (SIRT6) suppresses pancreatic cancer by regulating Lin28b, a microRNA pathway. Loss of SIRT6 promotes PDAC progression and metastasis, identifying a therapeutic target in a subset of patients.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Chromatin remodeling proteins are often dysregulated in cancer.
  • The role of these proteins in tumorigenesis, particularly in pancreatic ductal adenocarcinoma (PDAC), is not well understood.

Purpose of the Study:

  • To investigate the epigenetic role of Sirtuin 6 (SIRT6) in the suppression of pancreatic ductal adenocarcinoma (PDAC).
  • To identify the molecular mechanisms by which SIRT6 influences PDAC progression and metastasis.

Main Methods:

  • Investigated the function of SIRT6 in PDAC using molecular and epigenetic analyses.
  • Examined the regulation of Lin28b and let-7 microRNA pathway in response to SIRT6 activity.
  • Analyzed histone modifications and transcription factor recruitment at the Lin28b promoter.

Main Results:

  • SIRT6 inactivation accelerates PDAC progression and metastasis.
  • SIRT6 loss leads to Lin28b upregulation via histone hyperacetylation and Myc recruitment at the Lin28b promoter.
  • This epigenetic program is observed in 30%-40% of PDAC cases, correlating with poor prognosis and Lin28b dependence.

Conclusions:

  • SIRT6 acts as a tumor suppressor in PDAC.
  • The identified SIRT6-Lin28b epigenetic pathway is crucial for PDAC development and represents a potential therapeutic target for a defined subset of patients.

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