Journal Article

IDDF2025-ABS-0178 Targeting aurkb mitigates colorectal cancer progression via kinase-independent regulation of PSAT1

Xie, Qingxin, Li, Yuyi, Meng, Xiangjun, Xu, Che

2025

Overview

BackgroundAurora kinase B (AURKB), a key mitotic regulator, is frequently overexpressed in multiple malignancies including colorectal cancer (CRC) and correlates with poor prognosis. However, clinical trials have shown limited efficacy of AURKB inhibitors, indicating unrecognized oncogenic mechanisms that warrant further exploration.MethodsThe expression pattern of AURKB and its prognostic significance were explored in CRC tissues from our center and GEO cohort. The oncogenic roles of AURKB were demonstrated by proliferation and apoptosis assays. RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were performed to determine the downstream targets of AURKB. Mass spectrometry, Co-IP, RIP-qPCR, and mRNA stability assays were conducted to delineate the interplay and potential mechanisms involving AURKB, heterogeneous nuclear ribonucleoprotein M (HNRNPM), and phosphoserine aminotransferase 1 (PSAT1). The role of the AURKB/PSAT1 axis in CRC was further validated through in vivo rescue experiments.ResultsAURKB is highly expressed in CRC tissues and significantly correlates with unfavorable prognosis (IDDF2025-ABS-0178 figure 1. The expression pattern and prognostic significance of AURKB in CRC). Functional studies demonstrate that AURKB knockdown suppresses CRC proliferation and induces apoptosis (IDDF2025-ABS-0178 figure 2. AURKB depletion inhibits CRC proliferation and induces apoptosis). RNA-seq and GSEA reveal that AURKB regulates serine/glycine metabolism. Subsequent experiments show that AURKB depletion reduces PSAT1 expression and serine biosynthesis, an effect not observed with the kinase inhibitor AZD2811, suggesting a kinase-independent mechanism (IDDF2025-ABS-0178 figure 3. AURKB knockdown attenuates PSAT1 expression and serine biosynthesis). Mechanistically, AURKB interacts with HNRNPM and disrupts its binding to PSAT1 mRNA, thereby attenuating HNRNPM-mediated mRNA degradation and enhancing PSAT1 protein levels (IDDF2025-ABS-0178 figure 4. AURKB inhibits HNRNPM-mediated PSAT1 mRNA degradation). In vivo, rescue experiments confirm that PSAT1 overexpression reverses the effects of AURKB depletion on CRC progression (IDDF2025-ABS-0178 figure 5. PSAT1 rescues the proliferation suppression induced by AURKB depletion).Abstract IDDF2025-ABS-0178 Figure 1The expression pattern and prognostic significance of AURKB in CRC[Figure omitted. See PDF]Abstract IDDF2025-ABS-0178 Figure 2AURKB depletion inhibits CRC proliferation and induces apoptosis[Figure omitted. See PDF]Abstract IDDF2025-ABS-0178 Figure 3AURKB knockdown attenuates PSAT1 expression and serine biosynthesis[Figure omitted. See PDF]Abstract IDDF2025-ABS-0178 Figure 4AURKB inhibits HNRNPM-mediated PSAT1 mRNA degradation[Figure omitted. See PDF]Abstract IDDF2025-ABS-0178 Figure 5PSAT1 rescues the proliferation suppression induced by AURKB depletion[Figure omitted. See PDF]ConclusionsThis study reveals a kinase-independent role for AURKB in CRC through its interaction with RNA-binding protein, redefining its therapeutic potential beyond kinase inhibition. These findings highlight the need for alternative targeting strategies, such as PROTAC-based AURKB degraders, or pharmacological inhibition of the AURKB/PSAT1 axis, to fully harness its role in CRC treatment.

• Publisher: BMJ Publishing Group LTD
• Subject: Apoptosis / Aurora kinase / Biosynthesis / Cancer / Clinical trials / Colorectal cancer / Colorectal carcinoma / Degradation / Gene set enrichment analysis / Kinases / Malignancy / Mass spectroscopy / mRNA stability / Phosphoserine / Phosphoserine aminotransferase / Prognosis / RNA-binding protein / Serine