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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11th International Conference on
Journal of Medical Oncology and Therapeutics | Volume 3
Atique U Ahmed et al., J Med Oncl Ther 2018, Volume 3
THERAPEUTIC STRESS INDUCED
CELLULAR PLASTICITY: A POSSIBLE
NEW MECHANISMS OF THERAPEUTIC
RESISTANCE IN GLIOBLASTOMA
Atique U Ahmed, Jack M Shiremen, Cheol H Park, Fatemeh
Atashi, Seamus Caragher, Louisa Warnky, Shivani Baisiwala
and Gina Lee
Northwestern University, USA
Glioma stem cells (GSCs), a rare population of cancer cells capable
of self-renewal, are known to underlie therapeutic resistance
in glioblastoma (GBM), the most common and aggressive adult
primary brain tumor. Previously, we have shown that the anti-glioma
chemotherapy temozolomide (TMZ) initiates remarkable plasticity
in glioma cells and promotes the conversion of differentiated glioma
cells to therapy resistant GSCs. Our initial investigation indicated that
Polycomb group protein EZH2 is critical for this therapy-induced cellular
plasticity. Genome-wide chromatin immunoprecipitation (ChIP) in parallel
with DNA sequencing analysis (ChIP-seq) revealed 1449 distinct regions
enriched for EZH2 binding, specifically at the promoter regions of several
key genes including PTPRT, CDK5R2, and Siglec6. Gene expression
microarray analysis showed that this binding decreased cognate gene
expression in an effort to activate the master transcription factor STAT3,
a key molecular factor in promoting the GSC niche. To further investigate
this plasticity-based adaptation, we next performed histone 3 lysine
27 acetylation (H3K27ac) enrichment analysis in order to mark the
transcriptionally active chromatin state on a genome wide scale before
and after exposure to TMZ. A significant number of distal H3K27ac peaks
were detected only after chemo- (n = 452) and radiotherapy (n= 1029),
indicating that H3K27ac was modified by anti-glioma therapies in a locus-
specific manner. Furthermore, a de novo motif analysis identified the
homeobox TF binding motif (p=0.025) enriched within the H3K27ac peak
surrounding sequences during therapy. By combining the transcriptome
analysis from patientderived xenograft models and GBM patient data
(TCGA) with theH3K27ac enrichedmarks, we have identified several novel
homeobox transcription factors, which may contribute to therapyinduced
cellular plasticity and adaptation response. These findings provide new
insight into the molecular mechanisms by which epigenetic plasticity
regulates the GSC niche and may improve our understanding of how GBM
cells resist current treatment modalities.
Atique U Ahmed is currently appointed as As-
sistant Professor of Cancer Biology and mem-
ber of the Lurie Comprehensive Cancer Center,
Northwestern University, Chicago IL USA. He
received his PhD in Molecular Medicine from
Mayo Graduate School, USA. He has over 60
publications that have been cited over 2500
times, and his/her publication H-index is 31 and
has been American Cancer Society Scholar.
BIOGRAPHY