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CHTOP Regulates ROS Homeostasis to Modulate Chemoresistance in Colorectal Cancer

ABSTRACT: Chemotherapy resistance remains a significant challenge in colorectal cancer (CRC) treatment, with disrupted reactive oxygen species (ROS) homeostasis playing a central role. We identify CHTOP as a key regulator of ROS levels and chemoresistance in CRC. Mechanistically, CHTOP regulates ROS homeostasis by interacting with Nrf2 and modulating its SUMOylation via the SENP3-containing 5FMC complex. Notably, CHTOP expression is tightly controlled by a ROS-dependent feedback loop. The PSIP1/p52 isoform inhibits CHTOP expression by disrupting HNRNPH1-dependent splicing, leading to CHTOP degradation via nonsense-mediated decay (NMD). Meanwhile, ROS accumulation stabilizes SENP3, promoting the deSUMOylation and degradation of p52, thereby forming a ROS-SENP3-p52-CHTOP feedback loop. Thus, ROS levels both regulate and are regulated by CHTOP, maintaining redox balance. CHTOP downregulation in 5-FU-resistant CRC shifts cells into a higher-ROS steady state, which correlates with reduced 5-FU sensitivity. Both restoring CHTOP expression and inducing further depletion of CHTOP disrupt redox balance in 5-FU-resistant cells, reversing resistance and re-establishing sensitivity. These findings suggest that modulating CHTOP expression may offer a promising therapeutic strategy to overcome chemoresistance in CRC through redox regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313017 | GEO | 2026/08/15

REPOSITORIES: GEO

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Project description:Purpose: 5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death. Methods: ComboSyn software was used to study whether dual drug combinations synergistically promote each other and their dosage. CCK8, EdU and Annexin V/PI assays were used to study the cell proliferation and apoptosis of SW480 and HCT116 cells in response to SAL single-drug and dual-drug co-treatment. Cell cycle staining was used to assess cycle arrest. Wound healing and migration and invasion experiments were used to identify changes in migration and invasion capabilities under the influence of different drugs. Transcriptome sequencing is used to explore the molecular mechanisms of drugs. ROS fluorescence staining and MDA level measurement were used to confirm the changes in ferroptosis levels of SW480 and HCT116 cells after drug treatment. Nude xenograft mice were used to detect antitumor in vivo. Changes in the protein level expression of ferroptosis GPX4 and SLC7A11 were also determined in the treated cells.Results: SAL alone and combination of 5-FU were found to significantly increase cell mortality and apoptosis. At the same time, our results show that the blending of SAL and 5-FU not only inhibits the proliferation, migration, and invasion of CRC colorectal cancer cell lines in vivo and in vitro, but also promotes ferroptosis of CRC cell lines by downregulating the expression of GPX4 and SLC7A11. It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for CRC patients.Conclusions: SAL inhibiting colorectal cancer whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-fluorouracil.

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CHTOP Regulates ROS Homeostasis to Modulate Chemoresistance in Colorectal Cancer

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