Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1.

Jianing Ding,Peng Kuang

doi:10.3389/fonc.2021.664689

Abstract

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.

Highlights

The ubiquitination process functions to modulate the protein disposal and function in eukaryotic cell hemostasis [1, 2]
We showed that Homologous to the E6-AP Carboxyl Terminus 1 (HOIL-1), which was elevated in breast cancer, related to good prognosis in Estrogen receptor a (ERa) positive breast cancer, but correlated with poor outcome in endocrine-treated patients
These clinical data showed the consistent trend with previous reports that HOIL-1 might promote ERa signaling and endocrine resistance [23, 24]

Summary

Introduction

The ubiquitination process functions to modulate the protein disposal and function in eukaryotic cell hemostasis [1, 2]. E3 ubiquitin ligases promote the transfer of ubiquitin from the E2 ubiquitin conjugating enzymes to target protein substrates via their lysine residues [3]. The ubiquitination can be classifies as several types through the lysine residues on the ubiquitin proteins, including K63, K48, linear ubiquitination and mono-ubiquitination [2]. The ubiquitination process was firstly discovered as a target for proteins degradations [4]. HOIL-1 Stabilizes ERa that the ubiquitin systems play important role in protein functions in a group of regulatory pathways, such as signaling transduction, DNA damage response and endocytosis [5, 6]

Methods

Results

Conclusion