# Hsa_circ_0026782 Acts as a “Molecular Break” of CREB1‐Mediated Transcription by Promoting Its Phosphorylation at Ser142 That Prevents Keloid Progression

## TL;DR

A circular RNA called hsa_circ_0026782 prevents keloid progression by inhibiting CREB1 transcription activity through phosphorylation.

## Contribution

Identifies hsa_circ_0026782 as a novel molecular brake in keloid formation via CREB1 regulation.

## Key findings

- Hsa_circ_0026782 is downregulated in keloids and inhibits fibroblast proliferation and migration.
- Hsa_circ_0026782 binds CREB1, promotes its phosphorylation at Ser142, and reduces transactivation.
- The hsa_circ_0026782/CREB1 axis acts as a 'molecular break' to prevent keloid progression in vivo.

## Abstract

Keloids are a form of excessive fibrosis disease characterized by tumor‐like features, which are prone to recurrence. Circular RNAs play a role in various diseases, but its roles in keloids remain unclear. In this study, using high‐throughput RNA sequencing to compare keloids with normal scars, a novel circRNA, hsa_circ_0026782 is identified, whose expression is downregulated in keloids. The hsa_circ_0026782 inhibits the proliferation, migration, invasion, and apoptosis of primary human keloid fibroblasts, blocks the cell cycle in the S phase in vitro, and prevents keloid progression in vivo. Mechanistically, 1–90 nucleotides of hsa_circ_0026782 directly bind to the transcription factor CREB1. This interaction increases the exposure of the basic leucine zipper domain of CREB1 to enhance its dimerization. In addition, this interaction also promotes CREB1 phosphorylation at serine residue 142, inhibits the binding of CREB1 to the promoters or enhancers of its downstream target genes, and ultimately alters the transactivation of CREB1. The findings unveil that the hsa_circ_0026782/CREB1 axis acts as a transcriptional spatiotemporal “molecular break” in the formation of keloids, providing a new target for the therapy of keloids.

Model for the role of hsa_circ_0026782/p‐CREB1 (Ser142) played in keloid. Hsa_circ_0026782 is derived from back‐splicing of ITGA7 exon 4. When hsa_circ_0026782 binds to CREB1, the exposure of the bZIP domain and dimerization of CREB1 are promoted (upper left). Hsa_circ_0026782 increases the phosphorylation of Ser142 without affecting the expression, chromatin binding capacity, or phosphorylation at Ser133 of CREB1 (upper middle). Hsa_circ_0026782 turns high‐transactivated CREB1 into low‐transactivated CREB1, and decreases the transcription of downstream target genes (upper right). By this mechanism, hsa_circ_0026782 inhibits keloids both in vitro and in vivo (lower).