# Estrogen-Induced Hypermethylation Silencing of RPS2 and TMEM177 Inhibits Energy Metabolism and Reduces the Survival of CRC Cells

## TL;DR

Estrogen silences specific genes in colorectal cancer cells, disrupting energy production and reducing cancer cell survival.

## Contribution

The study identifies RPS2 and TMEM177 as novel epigenetic targets of estrogen in colorectal cancer.

## Key findings

- Estrogen silences RPS2 and TMEM177 through promoter hypermethylation, impairing mitochondrial function in CRC cells.
- Knockdown of RPS2 or TMEM177 reduces CRC cell viability by disrupting the OXPHOS pathway.
- ERα-dependent epigenetic reprogramming by estrogen leads to anti-growth effects in colorectal cancer.

## Abstract

What are the main findings?
Estrogen (E2) acts through ERα to suppress colorectal cancer cell growth by disrupting mitochondrial function and the oxidative phosphorylation (OXPHOS) pathway.The OXPHOS-associated genes RPS2 and TMEM177 are overexpressed and hypomethylated in CRC tissues, negatively correlate with ERα expression, and are epigenetically silenced by E2.

Estrogen (E2) acts through ERα to suppress colorectal cancer cell growth by disrupting mitochondrial function and the oxidative phosphorylation (OXPHOS) pathway.

The OXPHOS-associated genes RPS2 and TMEM177 are overexpressed and hypomethylated in CRC tissues, negatively correlate with ERα expression, and are epigenetically silenced by E2.

What are the implications of the main findings?
Silencing of RPS2 or TMEM177 phenocopies E2 treatment, leading to mitochondrial membrane depolarization, impaired OXPHOS, and reduced CRC cell viability.These findings reveal an ERα-dependent epigenetic–metabolic vulnerability in colorectal cancer that may be exploited for hormone- or epigenetic-based therapeutic strategies.

Silencing of RPS2 or TMEM177 phenocopies E2 treatment, leading to mitochondrial membrane depolarization, impaired OXPHOS, and reduced CRC cell viability.

These findings reveal an ERα-dependent epigenetic–metabolic vulnerability in colorectal cancer that may be exploited for hormone- or epigenetic-based therapeutic strategies.

Estrogen (E2, 17β estradiol) is recognized for its regulatory role in numerous genes associated with energy metabolism and for its ability to disrupt mitochondrial function in various cancer types. However, the influence of E2 on the metabolism of colorectal cancer (CRC) cells remains largely unexplored. In this study, we examined how E2 affects mitochondrial function and energy production in CRC cells, utilizing two distinct CRC cell lines, HCT-116 and SW480. Cell viability, mitochondrial function, and the expression of several genes involved in oxidative phosphorylation (OXPHOS) were assessed in estrogen receptor α (ERα)-expressing and ERα-silenced cells treated with increasing concentrations of E2 for 48 h. Our results indicated that the cytotoxicity of E2 against CRC cells is mediated by the E2/ERα complex, which induces disturbances in mitochondrial function and the OXPHOS pathway. Furthermore, we identified two novel targets, RPS2 and TMEM177, which displayed overexpression, hypomethylation, and a negative association with ERα expression in CRC tissue. E2 treatment in CRC cells reduced the expression of both targets through promoter hypermethylation. Treatment with 5-Aza-2-deoxycytidine increased the expression of RPS2 and TMEM177. This epigenetic effect disrupts the mitochondrial membrane potential (MMP), resulting in decreased activity of the OXPHOS pathway and inhibition of CRC cell growth. Knockdown of RPS2 or TMEM177 in CRC cells resulted in anti-cancer effects and disruption of MMP and OXPHOS. These findings suggest that E2 exerts ERα-dependent epigenetic reprogramming that leads to significant mitochondria-related anti-growth effects in CRC.