High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

Abstract

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/ NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment

“…Treatment with HA activates Nrf2 and induces Nrf2-target genes in bovine chondrocytes and human breast cancer cells, with increased phosphorylation of AKT or higher levels of p62, which competes with Nrf2 for binding to Keap1 (Komatsu et al, 2010), correlating with Nrf2 activation (Choi et al, 2022;Onodera et al, 2015;Ryoo et al, 2018). In addition, a hydrogel formulation of HA increased the levels of Nrf2 in frostbite-wounded skin tissues of Wistar rats (Joshi et al, 2021).…”

“…However, it was recently shown that ovarian cancer cell-derived high molecular-weight HA drives cholesterol efflux and depletion of lipid rafts from macrophages, which in turn drives IL-4 signaling and inhibition of IFNγ-induced gene expression ( Goossens et al, 2019 ). Treatment with HA activates Nrf2 and induces Nrf2-target genes in bovine chondrocytes and human breast cancer cells, with increased phosphorylation of AKT or higher levels of p62, which competes with Nrf2 for binding to Keap1 ( Komatsu et al, 2010 ), correlating with Nrf2 activation ( Choi et al, 2022 ; Onodera et al, 2015 ; Ryoo et al, 2018 ). In addition, a hydrogel formulation of HA increased the levels of Nrf2 in frostbite-wounded skin tissues of Wistar rats ( Joshi et al, 2021 ).…”

Role of Hyaluronic Acid in Selected Malignant Neoplasms in Women

“…In MCF-7 drug-resistant BC cells, an increase in HA production was observed due to the upregulation of HA synthase-2 (HAS2), while the upregulation of HAS2 contributed to the chemoresistance of cancer cells, as well as their ability to form drug-resistant spheres, through activation of the CD44/Nrf2 signaling pathway [75]. HAS2 levels were also correlated with the malignant phenotype of BC cells [53].…”

A genome-wide association study reveals novel SNP markers associated with resilience traits in two Mediterranean dairy sheep breeds

“…Moreover, LOC101110341 (HAS2) is involved in synthesis of hyaluronan, which is associated with mammary growth during gestation (Tolg et al, 2017). The latter gene along with ZHX2, DERL1, FAM83A and ATAD2 have been associated with intense symptoms, resistance to chemotherapy and bad prognosis of human breast cancer and metastatic canine mammary adenocarcinomas, implying interference in mammary cell growth and immune regulation (Kalashnikova et al, 2010;Klopfleisch et al, 2010;Lee et al, 2012;Fang et al, 2021;Choi et al, 2022). In accordance with the above, the suggestive significant SNP rs428540973 on chromosome 12, which was associated with SCC in Frizarta sheep, is located within RBP7; downregulation of its expression in human breast cancer has been associated with bad prognosis (Lin et al, 2022).…”