UBE2S promotes small cell lung cancer transformation and progression via monitoring metabolic remodeling and cell cycle

Sep 23, 2026

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Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid progression and poor survival. Although UBE2S has been studied in non-small cell lung cancer, its expression, function, and mechanisms in SCLC remain insufficiently defined. This study integrates multi-omics analyses and functional experiments to define how UBE2S drives metabolic reprogramming and cellular plasticity, and to explore therapeutic vulnerability in UBE2S-high SCLC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

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Introduction

Yan et al. Journal of Translational Medicine (2026) 24:783 [https://doi.org/10.1186/s12967-026-08146-6](https://doi.org/10.1186/s12967-026-08146-6) Journal of Translational Medicine RESEARCH Open Access UBE2S promotes small cell lung cancer transformation and progression via monitoring metabolic remodeling and cell cycle Xiaodong Yan1,2†, Shouqiang Pan3,4†, Jin Zhang5†, Kelei Mao1, Ruihao Yu6, Yiduo Xiong6, Haixia Huang1,7,8* and Yi Zhang4* Abstract Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid progression and poor survival. While the ubiquitin-conjugating enzyme E2 S (UBE2S) has been investigated in nonsmall cell lung cancer (NSCLC), its expression, functional roles, and underlying mechanisms in SCLC remain largely undefined. This study aims to elucidate the contribution of UBE2S to SCLC pathogenesis, metabolic reprogramming, and cellular plasticity. Methods UBE2S expression was analyzed using public databases (TCGA, GEO, LinkedOmics, TIMER, UALCAN, etc.) and validated by immunohistochemistry on lung cancer tissue microarrays. Gain-and loss-of-function experiments were conducted in SCLC cell lines. Multi-omics approaches—including single-cell RNA sequencing (scRNA-seq), proteomics, metabolomics, and immunoprecipitation-mass spectrometry (IP-MS)—were employed. Virtual screening was performed against the UBE2S structure to identify potential inhibitors. Statistical significance was assessed using Student’s t-test, ANOVA or adjusted p-values as appropriate. Results UBE2S was significantly upregulated in SCLC compared to NSCLC, with protein levels escalating from lungsquamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) to SCLC. Elevated UBE2S expression correlated with advanced stage in both LUAD and SCLC. Functional studies in vitro and in vivo demonstrated that UBE2S promotes SCLC proliferation and cell cycle progression by driving G1/S transition. ScRNA-seq revealed specific enrichment of UBE2S in SCLC cells and implicated it in NSCLC-to-SCLC phenotypic plasticity. Integrated proteomic and metabolomic analyses indicated that UBE2S remodels metabolism, activating pathways such as folate and amino acid biosynthesis. IP-MS identified the transcription factor DLX6 as a novel UBE2S interactor, with UBE2S overexpression reducing DLX6 †Xiaodong Yan, Shouqiang Pan and Jin Zhang contributed equally to this article. *Correspondence: Haixia Huang [haixiah@ccmu.edu.cn](haixiah@ccmu.edu.cn)[ ](haixiah@ccmu.edu.cn)Yi Zhang [zhangyixwhosp@xwh.ccmu.edu.cn](zhangyixwhosp@xwh.ccmu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Yan et al. Journal of Translational Medicine (2026) 24:783 Page 2 of 18 protein stability. Virtual screening integrated with functional assays identified Odetiglu

FAQs

What is the main purpose of the study?

To clarify how UBE2S contributes to SCLC pathogenesis, metabolic reprogramming, and cellular plasticity, and to identify related therapeutic implications.

How was UBE2S function and relevance to SCLC evaluated?

UBE2S expression was assessed using public databases and validated by immunohistochemistry, followed by gain- and loss-of-function experiments in SCLC cell lines and in vivo studies.

What mechanisms connect UBE2S to SCLC progression?

UBE2S promotes SCLC proliferation and cell cycle progression by driving G1/S transition, remodels metabolism through pathways such as folate and amino acid biosynthesis, and involves the transcription factor DLX6.

Sep 23, 2026

Uploaded by Mimi