121P - SIRT1 inhibition exhibits decreased pluripotency in cancer stem cells of glioma (121P)

Date 18 November 2017
Event ESMO Asia 2017 Congress
Session Poster lunch
Topics Basic Science
Central Nervous System Malignancies
Presenter mohita bhagat
Citation Annals of Oncology (2017) 28 (suppl_10): x35-x38. 10.1093/annonc/mdx657
Authors M. bhagat
  • Biochemistry, ALL INDIA INSTITUTE OF MEDICAL SCIENCE, 110029 - Delhi/IN

Abstract

Background

SIRT1, a class III histone deacetylase has cancer relevance because it regulates lifespan in multiple organisms and down-regulates p53 function through deacetylation. Cancer Stem Cells are a small subset of cells that are responsible for initiation, development, and recurrence of tumors. Therefore, it is important to understand the molecular mechanism of Cancer Stem Cells for translational applications in the treatment of patients with cancer. Role of SIRT1 in enhancing tumorigenesis has been well documented in many cancers. However, its functional role in glioma cancer stem cells is largely unknown.

Methods

In order to comprehend the role of SIRT1 in glioma cancer stem cells, we used EX-527, a nanomolar inhibitor of SIRT1 in three glioma Grade IV cell lines –U87MG, A172 and LN229. This was followed by expression analysis by Q-PCR, Immunofluorescence and Tumor sphere assay in glioma and cancer stem cells of glioma. Cell proliferation was assessed by XTT. Expression of genes in 20 grade IV glioma patient samples was compared to normal brain sample.

Results

U87MG, A172 and LN229 cells cultured in Stem Media exhibited an increase in SIRT1 expression compared to Normal media. XTT assay after EX527 treatment (10nM to 100µM) did not exhibit any change in cell proliferation compared to control cells in all the three glioma cell lines. SIRT1 inhibition exhibited a decreased expression of stemness markers –Sox-2 and Oct-4 and a decreased capacity to form gliomaspheres compared to the Control cells. Finally, we have correlated our in-vitro results with human GBM samples and found that SIRT1 and stemness markers correlated well in native tumor samples.

Conclusions

The results indicate a role of SIRT1 as a pluripotent marker in cancer stem cells of glioma. SIRT1 deacetylates p53 rendering it inactive and thus initaiting a ascade of events with oncogenic potential. Cancer stem cells are the cells responsible for drug resistance and tumor relapse Thus knowing the mechanism of SIRT1 action in cancer stem cells would open doors for more target specific therapy. Our study provides a functional interaction of SIRT1 with the stemness markers in cancer stem cells of glioma and glioma patient samples thus aiming for target specific approaches in glioma.

Clinical trial identification

Legal entity responsible for the study

All India institute of Medical Sciences

Funding

Indian Council of Medical Research

Funding

Indian Council of Medical Research

Disclosure

The author has declared no conflicts of interest.