ARIH1 Inhibition Promotes Microtubule Stability and Sensitizes Breast Cancer Cells to Microtubule-Stabilizing Agents.

Background: Microtubule dynamics play a pivotal role in cancer progression and response to chemotherapeutics. Identifying regulators of microtubule stability can provide new therapeutic targets and predictive biomarkers for cancer treatment. Methods: We investigated the role of ARIH1, an E3 ubiquitin ligase, in breast cancer by analyzing clinical datasets to assess its expression levels and prognostic significance. Functional studies were conducted in breast cancer cell lines to evaluate the impact of ARIH1 depletion on microtubule stability, MAP4 regulation, and paclitaxel sensitivity. Results: Clinical dataset analysis revealed that ARIH1 expression is significantly elevated in breast cancer tissues and correlates with poor prognosis and reduced recurrence-free survival. High ARIH1 expression stratifies patients into high-risk groups, underscoring its potential as a prognostic biomarker. Functional studies demonstrated that ARIH1 loss led to upregulation of MAP4, a microtubule-associated protein, resulting in microtubule stabilization via increased tubulin acetylation and enhanced spindle organization. This stabilization sensitized breast cancer cells to paclitaxel treatment, leading to reduced cell viability, impaired colony formation, and increased apoptosis in ARIH1-deficient cells. Conclusions: Our findings identify ARIH1 as a novel regulator of microtubule dynamics in breast cancer. ARIH1 suppression enhances paclitaxel sensitivity, highlighting its potential as both a therapeutic target and a biomarker for predicting treatment response and patient outcomes in breast cancer.