Y‐box binding protein 1 stabilizes EP300 mRNA and promotes forkhead box C1 H3K27Ac to aggravate chondrocyte injury in osteoarthritis

TL;DR

This study shows how YBX1 protein helps EP300 mRNA stability, leading to increased FOXC1 expression and worsened chondrocyte damage in osteoarthritis.

Contribution

The novel finding is that YBX1 stabilizes EP300 mRNA to promote FOXC1 H3K27Ac enrichment and chondrocyte injury in osteoarthritis.

Findings

YBX1 binds to EP300 mRNA and increases its stability in chondrocytes.

EP300 promotes H3K27Ac enrichment at the FOXC1 promoter, elevating FOXC1 expression.

YBX1 overexpression worsens IL-1β-induced chondrocyte apoptosis and inflammation.

Abstract

Chondrocyte abnormalities play an important role in osteoarthritis (OA), and forkhead box C1 (FOXC1) expression is related to OA progression. Nonetheless, the molecular mechanisms underlying the action of FOXC1 in chondrocytes remain unclear. Rats were subjected to anterior cruciate ligament transection (ACLT) to establish an in vivo OA model, and chondrocytes were subjected to interleukin (IL)‐1β to establish an in vitro OA model. Pathological changes in rat cartilage tissues were evaluated using hematoxylin–eosin and safranin O staining. H3K27Ac enrichment in the FOXC1 promoter was analyzed using chromatin immunoprecipitation. Interactions between EP300 and Y‐box binding protein 1 (YBX1) were validated using RNA immunoprecipitation and RNA pull‐down assay. The expression of YBX1, EP300, and FOXC1 was elevated in ACLT rats and IL‐1β‐induced chondrocytes. FOXC1 knockdown inhibited apoptosis and inflammatory response in IL‐1β‐induced chondrocytes. EP300 bound to FOXC1 promoter and promoted H3K27Ac enrichment in the FOXC1 promoter. Additionally, YBX1 bound to EP300 mRNA and enhanced EP300 mRNA stability. YBX1 overexpression promoted cell apoptosis and inflammation of IL‐1β‐induced chondrocytes, but was reversed by FOXC1 downregulation. YBX1 enhances EP300 mRNA stability and elevates FOXC1 expression by mediating FOXC1 H3K27Ac to promote IL‐1β‐induced chondrocyte apoptosis and inflammation, thereby exacerbating chondrocyte injury in OA.

In this study, YBX1 binds to EP300 mRNA and enhances its stability and expression. Subsequently, EP300 binds to the FOXC1 promoter and promotes the enrichment of H3K27Ac at the FOXC1 promoter to elevate FOXC1 expression, ultimately regulating IL‐1β‐induced chondrocyte damage and promoting the progression of osteoarthritis.

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