# circACTN4 promotes breast cancer cell cycle progression and oncogenesis via c-MYC induced histone H4 acetylation

## TL;DR

This study shows that circACTN4 promotes breast cancer by increasing histone acetylation through c-MYC, offering a new potential target for diagnosis and treatment.

## Contribution

The paper reveals a novel mechanism where circACTN4 promotes breast cancer via c-MYC-induced histone H4 acetylation.

## Key findings

- circACTN4 is highly expressed in breast cancer cells and tissues and is linked to poor prognosis.
- circACTN4 enhances cell proliferation and tumorigenesis by upregulating c-MYC and increasing histone H4 acetylation.
- Downregulating circACTN4 induces G1/S cell cycle arrest and reduces cancer cell growth.

## Abstract

Accumulating studies have shown the important role of circular RNAs (circRNAs) in the oncogenesis and metastasis of various cancers. We previously reported that circACTN4 could bind with FUBP1 to promote tumorigenesis and the development of breast cancer (BC) by increasing the expression of MYC. However, its exact molecular mechanism and biological function have not been fully elucidated.

Here, Circular RNA microarray analysis was conducted in 3 pairs of BC and paracancerous tissues. The expression of circACTN4 in BC cells and tissues was detected via reverse transcription‒quantitative PCR (RT‒qPCR). Cell Counting Kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), transwell migration, and invasion assays were performed to further detect the biological functions of circACTN4 in BC cells. Xenograft models were used to investigate the in vivo role of circACTN4. Fluorescence in situ hybridization, Chromatin immunoprecipitation (ChIP)‒qPCR, coimmunoprecipitation, fluorometric, western blot, and rescue experiments were performed to explore the mechanism of circACTN4.

Our results revealed that circACTN4 was highly expressed in BC cells and tissues. The upregulated expression of circACTN4 was significantly related to the T stage and TNM stage and poor prognosis of patients with BC. circACTN4 was located primarily in the nucleus of BC cells. Upregulation of circACTN4 significantly increased the proliferation, invasion, and growth of BC cells, whereas the downregulation of circACTN4 exerted the opposite effects and induced G1/S cell cycle arrest. Mechanistically, we showed that circACTN4 could upregulate the expression of MYC and that MYC might interact with TIP60 histone acetyltransferase to increase the recruitment of TIP60 to MYC target genes and histone H4 acetylation (AcH4), thus promoting the progression of the breast cancer cell cycle and tumorigenesis.

Taken together, our findings reveal for the first time a new mechanism by which circACTN4 could promote oncogenesis and the development of BC by increasing the AcH4 of MYC target genes via TIP60. Therefore, circACTN4 could be a novel target for BC diagnosis and remedy.