# Calcium and Cadmium Activate ESRRB to Mediate Cell Stemness and Pluripotency

## TL;DR

Calcium and cadmium activate ESRRB, a receptor involved in cell stemness and pluripotency, with cadmium mimicking calcium's effects.

## Contribution

This study identifies calcium as a natural ligand for ESRRB and reveals cadmium's ability to mimic calcium in activating ESRRB.

## Key findings

- Calcium and cadmium increase expression of ESRRB-regulated genes, which is blocked by an ESRRB antagonist.
- Cadmium enhances ESRRB nuclear localization and RNA polymerase recruitment to ERREs, promoting stemness and proliferation.
- Molecular docking suggests metal interaction sites in ESRRB's ligand-binding domain.

## Abstract

Estrogen-related receptor beta (ESRRB) is thought to be an orphan receptor that functions as a transcription factor, pioneer factor, and mitotic bookmarker to regulate cell stemness, pluripotency, and differentiation. This study (1) investigates whether calcium and cadmium activation of ESRRB regulates signaling pathways of stemness and pluripotency, (2) explores the transcriptomic and biological alterations of metal activation of ESRRB, and (3) reveals the underlying mechanisms by which metals activate ESRRB. In HEK293T cells, treatment with calcium and cadmium increased the expression of ESRRB-regulated genes that was blocked by an ESRRB antagonist. In the breast cancer cell line MDA-MB-453, treatment with calcium, cadmium, or a synthetic agonist also increased the expression of ESRRB-regulated genes that was blocked by the antagonist, enhanced ESRRB nuclear localization, increased the recruitment of RNA polymerase 2 to estrogen-related receptor response elements (ERRE), enhanced cell stemness and proliferation pathways, and induced the expression of estrogen receptor alpha (ESR1 or Erα). Mutational analysis and molecular docking identified potential metal interaction sites within ESRRB’s ligand-binding domain. Together, these results suggest calcium acts as a natural ligand for ESRRB and cadmium, which mimics calcium, activate ESRRB to mediate cell stemness and pluripotency.