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

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.