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Cholesterol activates the Wnt/PCP-YAP signaling in SOAT1-targeted treatment of colon cancer.

ABSTRACT: Intracellular free cholesterol can be converted to cholesteryl ester and stored as lipid droplets through SOAT1-mediated esterification. Compelling evidence implicate targeting SOAT1 as a promising therapeutic strategy for cancer management. Herein, we demonstrate how targeting SOAT1 promotes YAP expression by elevating cellular cholesterol content in colon cancer cells. Results revealed that cholesterol alleviates the inhibitory effect of LRP6 on the Wnt/PCP pathway by impeding the interaction of LRP6 with FZD7. Subsequently, FZD7-mediated PCP signaling directly elevated YAP expression by activating RhoA. Nystatin-mediated cholesterol sequestration significantly inhibited YAP expression under SOAT1 inhibition. Moreover, nystatin synergized with the SOAT1 inhibitor avasimibe in suppressing the viability of colon cancer cells in vitro and in vivo. The present study provides new mechanistic insights into the functions of cholesterol metabolism on growth signaling pathways and implicates a novel strategy for cholesterol metabolic-targeted treatment of colon cancers.

SUBMITTER: Xu H

PROVIDER: S-EPMC7910478 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Cholesterol activates the Wnt/PCP-YAP signaling in SOAT1-targeted treatment of colon cancer.

Xu Huanji H Xia Hongwei H Zhou Sheng S Tang Qiulin Q Bi Feng F

Cell death discovery 20210226 1

Intracellular free cholesterol can be converted to cholesteryl ester and stored as lipid droplets through SOAT1-mediated esterification. Compelling evidence implicate targeting SOAT1 as a promising therapeutic strategy for cancer management. Herein, we demonstrate how targeting SOAT1 promotes YAP expression by elevating cellular cholesterol content in colon cancer cells. Results revealed that cholesterol alleviates the inhibitory effect of LRP6 on the Wnt/PCP pathway by impeding the interaction ...[more]

PMID: 33637695

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Project description:Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41-positive thrombocytes. rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a-mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b, wnt11f2, fzd7a, and vangl2. Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism.

Dataset Information

Cholesterol activates the Wnt/PCP-YAP signaling in SOAT1-targeted treatment of colon cancer.

Publications

Cholesterol activates the Wnt/PCP-YAP signaling in SOAT1-targeted treatment of colon cancer.

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