hTERT Promotes CRC Proliferation and Migration by Recruiting YBX1 to Increase NRF2 Expression

Abstract

High human telomerase reverse transcriptase (hTERT) expression is related to severe Colorectal Cancer (CRC) progression and negatively related to CRC patient survival. Previous studies have revealed that hTERT can reduce cancer cellular reactive oxygen species (ROS) levels and accelerate cancer progression; however, the mechanism remains poorly understood. NFE2-related factor 2 (NRF2) is a molecule that plays a significant role in regulating cellular ROS homeostasis, but whether there is a correlation between hTERT and NRF2 remains unclear. Here, we showed that hTERT increases CRC proliferation and migration by inducing NRF2 upregulation. We further found that hTERT increases NRF2 expression at both the mRNA and protein levels. Our data also revealed that hTERT primarily upregulates NRF2 by increasing NRF2 promoter activity rather than by regulating NRF2 mRNA or protein stability. Using DNA pull-down/MS analysis, we found that hTERT can recruit YBX1 to upregulate NRF2 promoter activity. We also found that hTERT/YBX1 may localize to the P2 region of the NRF2 promoter. Taken together, our results demonstrate that hTERT facilitates CRC proliferation and migration by upregulating NRF2 expression through the recruitment of the transcription factor YBX1 to activate the NRF2 promoter. These results provide a new theoretical basis for CRC treatment.

5-Methylcytosine (m5C) modification in peripheral blood immune cells is a novel non-invasive biomarker for colorectal cancer diagnosis

“…One study reported that YBX1, the “readers” of m 5 C modification, activated NF signaling pathway in CRC ( 38 ). Moreover, the transcription factor YBX1 enhanced the expression of NRF2 by binding to its promoter region, promoting the proliferation of CRC cells ( 39 ). YBX1 also served as a mediator of signaling in the EGFR-RAS-MAPK axis ( 40 ).…”

The role of cycloastragenol at the intersection of NRF2/ARE, telomerase, and proteasome activity

“…On the other hand, hTERT G4-targeting small molecule (RG1603), or pharmacological inhibitor of hTERT (costunolide) and siRNA-mediated depletion of hTERT expression resulted in inhibition of NRF2 and HO-1 expression in glioblastoma and prostate cancer [86,87]. Interestingly, hTERT was found to be primarily upregulated NRF2 by increasing NRF2 promoter activity rather than by regulating NRF2 mRNA or protein stability in colon cancer cells [88]. Considering our results, which revealed that CA increased both NRF2, telomerase, and proteasome activity, we aimed to identify the underlying mechanism in the next step.…”

The role of Cycloastragenol at the intersection of Nrf-2/ARE, telomerase, and proteasome activity

“…On the other hand, hTERT G4-targeting small molecule (RG1603), or pharmacological inhibitor of hTERT (costunolide) and siRNA-mediated depletion of hTERT expression resulted in inhibition of Nrf-2 and HO-1 expression in glioblastoma and prostate cancer (Ahmad et al, 2016; Song et al, 2019). Interestingly, hTERT was found to be primarily upregulated Nrf-2 by increasing Nrf-2 promoter activity rather than by regulating Nrf-2 mRNA or protein stability in colon cancer cells (Gong et al, 2021). Considering our results, which revealed that CA increased both Nrf-2, telomerase, and proteasome activity, we aimed to identify the underlying mechanism in the next step.…”