Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Abstract

The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelialmesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.

The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

“…The tumour suppressor RARRES3 emerged as a likely important mediator of immune modulation. RARRES3 has previously been shown to attenuate breast cancer progression via lipid-related mechanisms including its intrinsic phospholipase A1/A2 activity16 and palmitoylation17. Our findings extend this functional repertoire by identifying a novel regulatory role as an endogenous inhibitor of the IP (but not the CP) subunit expression.…”

“…Co-expression patterns indicate a role for the retinoic acid receptor responder protein 3 ( RARRES3 ). This gene encodes a multi-functional enzyme associated with varied metastasis suppressing mechanisms including intrinsic phospholipase A1/A2 activity16 and palmitoylation of Wnt/β-catenin signaling molecules17.…”

Transcriptomic analysis of human norovirus NS1-2 protein highlights a multifunctional role in murine monocytes

“…When looking at the class of proteins that are altered by presence of HuNoV NS1-2, phosphoproteins made up 53% and acetylation constitutes 25% of the DE genes (data not shown). This suggests that the ordered region of the NS1-2 protein may play a role in regulating phosphorylated and/or acetylated proteins, as shown for mammalian proteins with the H-box and NC motif, such as LRAT and retinoic acid responder 3 (RARRES3) [62]. When looking at the cellular placement of the proteins altered by HuNoV NS1-2, 26% of the proteins are cytoplasmic and 29% are nuclear.…”

PRDM16 inhibits cell proliferation and migration via epithelial to mesenchymal transition by directly targeting pyruvate carboxylase in papillary thyroid cancer

“…We used RNA-sequencing technique and found seven genes which have been reported to be related with EMT process. They were RRAD (39), PTGES (40), PIM1 (41), LYPD3 (42), PTP4A (43), RARRES3 (44,45) and PC. In 2012, Sun Yeon Lee et al (46) reported a study on the relationship between PC and EMT in breast tumor cell line MCF-7.…”