Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-08-18 DOI:10.1016/j.bbadis.2025.168023

Erika Matsuda , Shiho Hasebe , Takashi Matsuzaka , Akio Hayashi , Hiroshi Ohno , Kaori Motomura , Shotaro Sakka , Susumu Kohno , Hayato Muranaka , Minako Yamamura , Asuka Suzuki , Yoshinori Takeuchi , Yoshinori Osaki , Takafumi Miyamoto , Motohiro Sekiya , Hirohito Sone , Naoya Yahagi , Yoshimi Nakagawa , Satoshi Nitta , Shuya Kandori , Hitoshi Shimano

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引用次数: 0

Abstract

Objective

Increased de novo fatty acid (FA) synthesis is a hallmark of cancer. ELOVL FA elongase 6 (ELOVL6) catalyze chain elongation of C16 saturated and monounsaturated FAs into C18 species and has been implicated in several cancers. This study investigated the role of ELOVL6 in bladder cancer (BC).

Methods

ELOVL6 expression was compared between BC and nontumor tissues. Human BC cell lines with ELOVL6-knockdown were assessed for proliferation and tumor growth. Metabolic and molecular alterations induced by ELOVL6 inhibition were analyzed using lipidomics and transcriptomics.

Results

ELOVL6 expression was significantly higher in BC tissues than in controls. In fibroblast growth factor receptor 3 (FGFR3)-mutant BC cell lines, ELOVL6 knockdown suppressed cell growth in vitro and tumor progression in vivo. Lipidomic analysis showed a marked reduction in phosphatidylethanolamine following ELOVL6 knockdown, which was accompanied by lower mitochondrial complex I and II protein levels and impaired mitochondrial oxidative phosphorylation (OXPHOS). RNA sequencing revealed that mitochondrial dysfunction resulting from ELOVL6 knockdown triggered changes in extracellular matrix (ECM) remodeling gene expression and activation of the ECM-integrin-focal adhesion kinase (FAK) pathway, likely as a compensatory response to reduced cell proliferation.

Conclusion

ELOVL6 regulates lipid composition to preserve mitochondrial function, supporting cell growth and tumorigenesis in FGFR3-mutated BC. Targeting ELOVL6 may represent a novel therapeutic strategy for treating BC, particularly in tumors driven by FGFR3 mutations.

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在fgfr3突变的膀胱癌细胞中，抑制ELOVL6活性损害线粒体呼吸功能并抑制肿瘤进展

目的：新生脂肪酸（FA）合成增加是癌症的一个标志。ELOVL FA延长酶6 （ELOVL6）催化C16饱和和单不饱和脂肪酸链延伸到C18物种，并与几种癌症有关。本研究探讨ELOVL6在膀胱癌（BC）中的作用。方法比较BC组织与非肿瘤组织中selovl6的表达。我们对elovl6敲低的人BC细胞系的增殖和肿瘤生长进行了评估。利用脂质组学和转录组学分析ELOVL6抑制引起的代谢和分子改变。结果selovl6在BC组织中的表达明显高于对照组。在成纤维细胞生长因子受体3 （FGFR3）突变的BC细胞系中，ELOVL6敲低抑制体外细胞生长和体内肿瘤进展。脂质组学分析显示，ELOVL6基因敲除后，磷脂酰乙醇胺显著减少，同时线粒体复合体I和II蛋白水平降低，线粒体氧化磷酸化（OXPHOS）受损。RNA测序显示，ELOVL6敲低导致的线粒体功能障碍引发了细胞外基质（ECM）重塑基因表达的变化和ECM-整合素-焦点粘附激酶（FAK）途径的激活，可能是对细胞增殖减少的代偿反应。结论elovl6调节脂质组成，维持线粒体功能，支持fgfr3突变的BC细胞生长和肿瘤发生。靶向ELOVL6可能是治疗BC的一种新的治疗策略，特别是在由FGFR3突变驱动的肿瘤中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.