STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Abstract

NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer (CRC). Silencing STRAP sensitized CRC cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of CRC cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which form repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 CRC clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP-NOTCH1-HES1 molecular axis as a CSC regulator in CRC, with potential implications to improve treatment of this disease.

Oncogenic STRAP Supports Hepatocellular Carcinoma Growth by Enhancing Wnt/β-Catenin Signaling

“…These results suggest that one mechanism by which elevated STRAP expression supports HCC growth is to shift the balance toward the induction of stem cell features. This observation is in line with the work of Jin and colleagues who showed that STRAP promotes stem cell features in several colorectal cancer cell lines (33). Besides its role in fine-tuning b-catenin signaling, STRAP has also been linked to various other cellular processes likely con-tributing to HCC cell viability (9,14).…”

“…In particular, Wnt/b-catenin-driven AXIN2 þ (31) and LGR5 þ (32) cells have been identified as stem cells that self-renew and give rise to mature hepatocytes. STRAP itself has also been linked to stemness in colorectal cancer (33). Therefore, loss of STRAP and the resulting reduction in b-catenin signaling may lead to reduced expression of stem/ progenitor cell markers.…”

The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells

“…The NOTCH pathway has been reported to modulate the homeostasis of cancer stem cell-like cells (CSCs) in colorectal cancer [43]. Miranda Brun et al found that HEY1 was associated with increased proliferation and stem cell characteristics in GBM cells [44].…”

Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer

“…Moreover, alterations in FBXW7 have been related to liver metastasis and prognosis of CRC . The expression of another WDR domain protein, STRAP, was increased in CRC and promoted stemness of CRC via regulation of NOTCH signaling . Other WDR domain proteins, such as WDR13, DCAF4L2, WDR48, Bop1, CIRH1A, DTL, and EIF3B, have also been shown to be involved in the development and progression of CRC .…”

“…[16][17][18] The expression of another WDR domain protein, STRAP, was increased in CRC and promoted stemness of CRC via regulation of NOTCH signaling. [19][20][21] Other WDR domain proteins, such as WDR13, DCAF4L2, WDR48, Bop1, CIRH1A, DTL, and EIF3B, have also been shown to be involved in the development and progression of CRC. [22][23][24][25][26][27][28] Recently, two WDR domain proteins, WDR5 and EDD, were successfully targeted by drug-like chemical probes.…”