ALYREF-Mediated Regulation of TBL1XR1 and KMT2E Synergistically Upregulates APOC1 - Contributing to Oxaliplatin Resistance in Esophageal Cancer

Sep 23, 2026

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Study investigates how ALYREF regulates TBL1XR1 and KMT2E to control APOC1 expression and thereby drive oxaliplatin (L-OHP) resistance in esophageal cancer. Gene and protein expression were measured with quantitative real-time PCR, Western blot, and immunohistochemistry. Molecular interactions were assessed using RNA immunoprecipitation, ChIP/ChIP-reChIP, RNA pulldown, and dual-luciferase assays, supported by an in vivo mouse model. Results show elevated APOC1 and ALYREF in resistant models, with ALYREF binding m5C sites on TBL1XR1 and KMT2E mRNAs to stabilize them and increase APOC1 transcription, enhancing L-OHP resistance.

LanguageEnglish

CategoryHealthcare

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Pages26

Reading Time1 h 6 min

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Materials and Methods

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[https://doi.org/10.4143/crt.2024.1091](https://doi.org/10.4143/crt.2024.1091) Cancer Res Treat. 2025;57(4):1064-1089 Original Article ALYREF-Mediated Regulation ofTBL1XR1 and KMT2E Synergistically UpregulatesAPOC1, Contributing to Oxaliplatin Resistance in Esophageal Cancer Jie Hu1 , Qilong Liu2 , Bi Feng1 , Yanling Lu1 , Kai Chen1 1Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 2Department of Gastroenterology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Purpose Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance. Materials and Methods The assessment of gene and protein expression was conducted through a combination of quantitative realtime polymerase chain reaction, Western blot, and immunohistochemical staining. Cell viability was assessed using the cell counting kit-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RNA immunoprecipitation, chromatin immunoprecipitation (ChIP), ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established. Results Expression levels of both APOC1 and ALYREF were elevated in L-OHP–resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the 5-methylcytosine (m5C) sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo. Conclusion This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC. Key words Esophageal neoplasms, Oxaliplatin resistance, ALYREF, TBL1XR1, KMT2E, H3K4me3 modification, APOC1 Introduction Esophageal cancer (EC) ranks among the most aggressive types of cancer with a high mortality rate worldwide [1] . Despite advancements in diagnostic and therapeutic approaches, including surgery, chemotherapy, radiotherapy, and targeted therapies, outcomes for patients with EC remain generally poor [2] . This is primarily due to the disease often being detected at an advanced stage and having a high likelihood of recurrence and metastasis [2] . Among the chemotherapeutic agents, oxaliplatin (L-OHP) has been widely used as a key component in the treatment of EC due to its efficacy in inducing cancer cell apoptosis via DNA cross-linking and inhibition of DNA replication [3] . However, the development of resistance to L-OHP significantly limits its therapeutic effectiveness, posing a major challenge in the clinical management of EC [4]. Therefore, overcoming L-OHP resistance and enhancing the sensitivity of EC cells to L-OHP could be crucial strategies for improving treatment outcomes. Apolipoprotein C1 (APOC1) plays a crucial role in the metabolism of very low-density lipoprotein and high-density lipoprotein cholesterol [5] . Recent studies suggest that APOC1 may represent a promising therapeutic target in the treatment of solid tumors [6,7] . APOC1 enhanced glioma metastasis by promoting epithelial-mesenchymal transition and the activation of the STAT3 signaling pathway [7]. Additionally, APOC1 facilitated osteosarcoma progression via regulating mitochondrial carrier hom

FAQs

What problem does the study address in esophageal cancer?

The study addresses low treatment success caused by oxaliplatin resistance, which limits chemotherapy effectiveness and contributes to poor outcomes.

Which genes and mechanism are central to the proposed regulatory pathway?

ALYREF is reported to regulate TBL1XR1 and KMT2E, and this synergistically upregulates APOC1. ALYREF recognizes m5C sites on TBL1XR1 and KMT2E mRNAs to stabilize them and promote APOC1 expression.

How were the molecular interactions and functional effects validated?

Interactions were tested using RNA immunoprecipitation, ChIP/ChIP-reChIP, RNA pulldown, and dual-luciferase assays, and the regulatory role was further validated using an in vivo mouse model.

Sep 23, 2026

Uploaded by Bulrr