The NRF2-dependent transcriptional axis, XRCC5/hTERT drives tumor progression and 5-Fu insensitivity in hepatocellular carcinoma

Abstract

Human telomerase reverse transcriptase (hTERT) is highly expressed in many tumors and is essential for tumorigenesis and metastasis in multiple cancers. However, the molecular mechanisms underlying its high expression level in hepatocellular carcinoma (HCC) remain unclear. In this study, we identified X-ray repair cross-complementing 5 (XRCC5), a novel hTERT promoter-binding protein in HCC cells, using biotin-streptavidin-agarose pull-down assay. We found that XRCC5 was highly expressed in HCC cells, in which it transcriptionally upregulated hTERT. Functionally, the transgenic expression of XRCC5 promoted HCC progression and 5-fluorouracil resistance, whereas short hairpin RNA knockdown of XRCC5 had converse effects in vitro and in vivo. Moreover, hTERT overexpression reversed XRCC5 knockdown-or 5-fluorouracil (5-Fu)-mediated HCC inhibition. Mechanistically, nuclear-factor-erythroid-2-related factor 2 (NRF2) interacted with XRCC5, which in turn upregulated hTERT. However, the upregulation was insignificant when NRF2 was reduced, suggesting that the XRCC5-mediated hTERT expression was NRF2 dependent. The HCC patients with high expression levels of XRCC5 and hTERT had shorter overall survival times compared with those with low XRCC5 and hTERT levels in their tumor tissues. Collectively, our study demonstrates the molecular mechanisms of the XRCC5/NRF2/hTERT signaling in HCC metastasis, which will aid in the identification of novel strategies for the diagnosis and treatment of HCC.

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

“…In addition to the interrelationships of proteasome-hTERT and proteasome-NRF2 system, there are several studies about the bilateral relations between hTERT and NRF2. XRCC5 (X-ray repair crosscomplementing 5), a transcriptional regulator factor binding to the hTERT promoter, was reported to physically interact with NRF2, which in turn upregulated hTERT in an NRF2 dependent manner in hepatocellular carcinoma (HCC) cells [83]. Consistently, administration of (caption on next column) Fig.…”

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

“…In addition to the interrelationships of proteasome-hTERT and proteasome-Nrf-2 system, there are several studies about the bilateral relations between hTERT and Nrf-2. XRCC5 (X-ray repair cross-complementing 5), a transcriptional regulator factor binding to the hTERT promoter, was reported to physically interact with Nrf-2, which in turn upregulated hTERT in an Nrf-2 dependent manner in hepatocellular carcinoma (HCC) cells (Liu et al, 2022). Consistently, administration of DMF, an activator of Nrf-2 pathway, to mice resulted in significant elevation of TERT mRNA levels (Akino et al, 2019).…”

Cell Survival, Death, and Proliferation in Senescent and Cancer Cells: the Role of (Poly)phenols

“…Inhibition of the mTORC1 pathway and activation of Nrf2 are other mechanisms by which curcumin could increase the lifespan of normal cells. Recent data have indeed shown that Nrf2 interacts with X-ray repair cross complementing 5 and regulates hTERT expression, increasing chromosome integrity and genome stability for long-term proliferation [ 139 ]. Overall, a multitude of in vivo, in vitro , and clinical studies have confirmed the protective role of curcumin via Nrf2 regulation, which in turn could maintain telomere integrity [ 118 , 140 ].…”