HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

Abstract

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.

Elevated HSPB1 Expression Is Associated with a Poor Prognosis in Glioblastoma Multiforme Patients

“…Studies have suggested that high HSPB1 expression predicts poor clinical outcomes in several cancers, including breast cancer, hepatocellular carcinoma, gastric cancer, lung cancer, and pancreatic cancer. [32][33][34][35][36] We also discovered that the expression of HSPB1 was elevated in a variety of cancers, including GBM. Consistent with previous reports, we found that patients with GBM who had elevated expression of HSPB1 had shorter OS, DSS, and PFI than those with lower HSPB1 expression.…”

STUB1 promotes the degradation of HSPB1 and induces ferroptosis in lung cancer cells

“…However, the role of STUB1 in regulating ferroptosis through ubiquitination in the development of lung cancer is still relatively rare. Recent studies have shown that HSPB1 functions as a ferroptosis suppressor in the context of ferroptosis, 26 where it promotes chemoresistance in breast cancer cells by inhibiting ferroptosis and modulating the NF‐κB signaling pathway 27 . Targeting HSPB1 for the regulation of ferroptosis also mitigates sorafenib resistance in hepatocellular carcinoma 24 .…”