Acetylation of ELF5 suppresses breast cancer progression by promoting its degradation and targeting CCND1

Xiahui Li,Kangkai Xia,Yanan Li,Bashir Ahmad,Huijian Wu,Yuxi Yang,Shujing Li,Bowen Li,Sattout Aman

doi:10.1038/s41698-021-00158-3

Abstract

E74-like ETS transcription factor 5 (ELF5) is involved in a wide spectrum of biological processes, e.g., mammogenesis and tumor progression. We have identified a list of p300-interacting proteins in human breast cancer cells. Among these, ELF5 was found to interact with p300 via acetylation, and the potential acetylation sites were identified as K130, K134, K143, K197, K228, and K245. Furthermore, an ELF5-specific deacetylase, SIRT6, was also identified. Acetylation of ELF5 promoted its ubiquitination and degradation, but was also essential for its antiproliferative effect against breast cancer, as overexpression of wild-type ELF5 and sustained acetylation-mimicking ELF5 mutant could inhibit the expression of its target gene CCND1. Taken together, the results demonstrated a novel regulation of ELF5 as well as shedding light on its important role in modulation of breast cancer progression.

Highlights

Breast cancer is one of the most common malignant tumors in women worldwide, and the incidence of breast cancer is still increasing[1,2]
Emerging evidence has revealed that proteins acetylation is involved in various biological events, including gene expression, DNA damage repair, cellular metabolism, cell cycle, signal transduction, and tumor metastasis16. p300 is one of the most representative lysine acetyltransferases (KATs) in mammalian cells
Hundreds of p300-acetylated substrates have been identified, e.g., β-catenin, STAT3, and HDAC1, and acetylation is a key form of posttranslational modifications (PTMs) for their functions[29,30,31,32]

Summary

Introduction

Breast cancer is one of the most common malignant tumors in women worldwide, and the incidence of breast cancer is still increasing[1,2]. Breast cancer accounts for 25–30% of female malignant tumors in the US and Asia, and it is the second leading cause of cancer death in women[3]. ELF5 inhibits the transcription of ER, FOXA1, EGFR, MYC, and other proliferationrelated genes, resulting in the suppression of estrogen sensitivity[7,8]. Lysine acetylation is a key form of PTMs that control gene expression, affecting a diverse set of disease signaling pathways in normal cells and during cancer progression[16,17,18]. Lysine acetylation affects protein functions through diverse mechanisms, and it plays an in increasingly important role in both physiological and pathological processes[16,21,22,23]. There is no study concerning the effects of PTMs on the regulation of ELF5

Methods

Results

Conclusion