Enhanced E6AP-mediated ubiquitination of ENO1 via LINC00663 contributes to radiosensitivity of breast cancer by regulating mitochondrial homeostasis

Radiotherapy has shown measurable efficacy in breast cancer (BC). Elucidating the mechanisms and developing effective strategies against resistance, which is a major challenge, is crucial. Mitochondria, which regulate ho-meostasis of the redox environment, have emerged as a radiotherapeutic target. However, the mechanism via which mitochondria are controlled under radiation remains elusive. Here, we identified alpha-enolase (ENO1), as a prognostic marker for the efficacy of BC radiotherapy. ENO1 enhances radio-therapeutic resistance in BC via reducing the production of reactive oxygen species (ROS) and apoptosis in vitro and in vivo through modulation of mitochondrial homeostasis. Moreover, LINC00663 was identified as an upstream regulator of ENO1, which regulates radiotherapeutic sensitivity by downregulating ENO1 expression in BC cells. LINC00663 regulates ENO1 protein stability by enhancing the E6AP-mediated ubiquitin-proteasome pathway. In BC patients, LINC00663 expression is negatively correlated with ENO1 expression. Among patients treated with IR, those who did not respond to radiotherapy expressed lower levels of LINC00663 than those sensitive to radiotherapy. Our work established LINC00663/ENO1 critical to regulate IR-resistance in BC. Inhibition of ENO1 with a specific inhibitor or supplement of LINC00663 could be potential sensitizing therapeutic strategies for BC.

Automated summary

Radiotherapy has demonstrated efficacy in breast cancer, but resistance remains a challenge. Mitochondria, as a crucial regulator of redox homeostasis, have emerged as a target for radiotherapy. This study identified ENO1 as a prognostic marker for radiotherapy efficacy in breast cancer. ENO1 reduces reactive oxygen species and apoptosis through modulation of mitochondrial homeostasis, leading to radiotherapeutic resistance. LINC00663 was identified as an upstream regulator of ENO1, and its downregulation enhances radiotherapeutic sensitivity in breast cancer by regulating ENO1 protein stability.