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

Abstract

Background: 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. Herein, we sought to determine the relationship of hTERT and NRF2 in the progression of CRC and to elucidate the underlying molecular mechanisms.Methods: qPCR, Western blot, Immunohistochemistry, immunofluorescence assays were used to detect the mRNA and protein expression of hTERT, NRF2 and YBX1 in CRC cell lines and tissues.CCK8 and colony formation were used to detect the proliferation of CRC cells, transwell assay was used to detect the migration of CRC cells. Dual-luciferase reporter assays were used to detect the promoter activity of NRF2. DNA pull-down/MS analysis was used to identify NRF2 promoter binding proteins. ChIP-qPCR was used to detect the YBX1binding sequences of NRF2 promoter.Results: Both hTERT and NRF2 are highly expressed in CRC tissues and associated with poor diagnosis. hTERT increases NRF2 expression at both the mRNA and protein levels. hTERT increases CRC proliferation and migration by inducing NRF2 upregulation. Moreover, hTERT primarily upregulates NRF2 by increasing NRF2 promoter activity rather than by regulating NRF2 mRNA or protein stability, and hTERT recruits YBX1 to upregulate NRF2 promoter activity thus increases NRF2 expression and enhances CRC proliferation and migration.Conclusions: hTERT facilitates CRC proliferation and migration by upregulating NRF2 expression through the recruitment of the transcription factor YBX1 to activate the NRF2 promoter.

AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation

“…Early studies have reported that AMPK activation enhances cellular antioxidant potential by activating the transcriptional activity of Nrf2 ( Garcia and Shaw, 2017 ; Xu et al, 2020 ). Nrf2 is a member of the Cap’n’Collar (CNC) family of basic leucine zipper (bZIP) transcription factors, which activates the endogenous antioxidant defense system through translocation into the nucleus, thus combating inflammation and oxidative stress ( Tonelli et al, 2018 ; Lyu et al, 2020 ; Gong et al, 2021 ; Tan et al, 2021 ). Inflammation causes oxidative stress; in turn, oxidative stress also boosts the production of inflammatory cytokines through activation of proinflammatory pathways, including the known Nod-like Receptor Protein 3 (NLRP3) inflammasome pathway ( Zeng et al, 2017 ).…”