All ETDs from UAB

Advisory Committee Chair

Pran K Datta

Advisory Committee Members

Ralph D Sanderson

Rosa A Serra

Keshav K Singh

Sunil Sudarshan

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Emerging data suggest that Serine-Threonine Kinase Receptor-Associated Protein (STRAP), a scaffold protein, is upregulated in several human cancers. Here, we report a novel oncogenic function of STRAP, maintaining the colorectal cancer stem cell subpopulations in a heterogeneous mixture and drug resistance by suppressing the formation of polycomb repressive complex 2 (PRC2) and epigenetically activating Notch signals in human colorectal cancer. Our data show that depletion of STRAP by shRNA sensitizes the colorectal tumor cells to drug-induced apoptosis. STRAP knockdown also contributes to the reduced stem-like phenotype of cells, indicated by reduced expression of CSC signatures and Notch signaling regulators in vitro and by diminished tumorigenesis in vivo in mice. The results of epigenetic studies revealed that the loci of some of the Notch activators are highly occupied by H3K27me3 producing repressive chromatin environments upon STRAP knockdown. STRAP exerts its inhibitory effect on assembling PRC2 complex by competitively disrupting the EZH2-SUZ12 association. Overall, our findings unravel a novel molecular axis, STRAP/Notch1/HES1 as a regulator of CRC CSC phenotype and drug resistance. Furthermore, we generated Strap conditional knockout mice (StrapIEKO) and crossed with ApcMin/+ mice to study the effect of Strap deletion on APC induced tumorigenesis. Conditional deletion of Strap in a mouse model of Apc-mediated intestinal polyps demonstrated that STRAP was required for polyp formation in both small intestine and colon. Colon tumors from ApcMin/+;StrapIEKO mice displayed a decrease in β-catenin nuclear localization and downregulation Wnt target genes. STRAP knockdown in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity. We established a novel mechanism in which STRAP can associate with MEK and promote the binding between MEK and ERK1/2. Given that MEK/ERK signaling was found to regulate Wnt/β-catenin signaling, our results suggested that STRAP can indirectly regulate the activity of Wnt/β-catenin signaling through MEK/ERK signaling. We also found that STRAP is a novel target of Wnt/β-catenin signaling as ChIP revealed binding sites of β-catenin/TCF4 complex on STRAP promoters. Altogether, this study indicated that STRAP plays an essential role in the crosstalk between Wnt/β-catenin and MEK/ERK signaling pathways.

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