HBXIP induces anoikis resistance by forming a reciprocal feedback loop with Nrf2 to maintain redox homeostasis and stabilize Prdx1 in breast cancer

Abstract

Anoikis resistance is an essential prerequisite for tumor metastasis, but the underlying molecular mechanisms remain unknown. Herein, we report that the oncoprotein hepatitis B X-interacting protein (HBXIP) is prominently upregulated in breast cancer cells following ECM detachment. Altering HBXIP expression can impair the anchorage-independent growth ability of tumor cells. Mechanistically, HBXIP, which binds to Kelch-like ECH-associated protein 1 (Keap1) to activate nuclear factor E2-related factor 2 (Nrf2), contains a cis-acting antioxidant response element (ARE) in the gene promoter and is a target gene of Nrf2. The HBXIP/Nrf2 axis forms a reciprocal positive feedback loop that reinforces the expression and tumor-promoting actions of each protein. In response to ECM detachment, Nrf2 reduces reactive oxygen species (ROS) accumulation, protects the mitochondrial membrane potential and increases cellular ATP, GSH and NADPH levels to maintain breast cancer cell survival. Meanwhile, the reinforcement of HBXIP induced by Nrf2 inhibits JNK1 activation by inhibiting ubiquitin-mediated degradation of Prdx1, which also plays an essential role in promoting ECM-detached cell survival. Furthermore, a strong positive correlation was identified between HBXIP expression and Prdx1 expression in clinical breast cancer tissues and TCGA Pan-Cancer Atlas clinical data of breast invasive carcinoma based on the cBioPortal cancer genomics database. Co-expression of HBXIP and Prdx1 predicts a poor prognosis for breast cancer patients. Collectively, our findings reveal a significant mechanism by which the HBXIP/Nrf2 feedback loop contributes to anoikis resistance by maintaining redox homeostasis and inhibiting JNK1 activation and support the likely therapeutic value of the HBXIP/Nrf2 axis in breast cancer patients.

A novel anoikis-related gene signature predicts prognosis in patients with head and neck squamous cell carcinoma and reveals immune infiltration

“…Anoikis is a form of programmed cell death, which is essential for the survival of tumor cells after detachment from the extracellular matrix (ECM) (Xiao et al, 2019;Zhou et al, 2022). The generation of anoikis resistance in aggressive tumor cells has been identified as a key factor in tumor progression (Berezovskaya et al, 2005;Kim et al, 2012;Yu et al, 2022).…”

Identification and Validation of the Anoikis-Related Gene Signature as a Novel Prognostic Model for Cervical Squamous Cell Carcinoma, Endocervical Adenocarcinoma, and Revelation Immune Infiltration

“…Anoikis is a special apoptotic that is a consequence of the loss of or improper cell adhesion, which is paramount for the survival of tumor cells following separation from the extracellular matrix (ECM) [ 14 , 15 , 16 ]. Previous studies have found that an anti-anoikis mechanism in cancer cells is pivotal to cancer progression [ 17 , 18 ]. In recent years, although a multitude of mechanisms of anoikis in tumors have been proposed and validated, the role of prognostic molecules of anoikis-related genes underlying tumors remains to be defined.…”

Exploration and identification of anoikis-related genes in polycythemia vera

“…Some studies suggested anoikis occurred through intrinsic/extrinsic pathways and could be triggered by several intracellular signals such as DNA damage and endoplasmic reticulum stress (Li et al, 2019;Zhi et al, 2022). Anoikis is essential for cancer cell survival through the detachment from ECM, and anoikis resistance is a key factor in cancer invasion and metastasis (Berezovskaya et al, 2005;Kim et al, 2012;Kakavandi et al, 2018;Xiao et al, 2019;Yu et al, 2022;Zhou et al, 2022).…”