2. Academic Validation
  3. Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells

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

  • Biochim Biophys Acta Mol Basis Dis. 2025 Aug 18;1871(8):168023. doi: 10.1016/j.bbadis.2025.168023.
Erika Matsuda 1,  Shiho Hasebe 1,  Takashi Matsuzaka 2,  Akio Hayashi 1,  Hiroshi Ohno 1,  Kaori Motomura 1,  Shotaro Sakka 3,  Susumu Kohno 4,  Hayato Muranaka 4,  Minako Yamamura 5,  Asuka Suzuki 1,  Yoshinori Takeuchi 6,  Yoshinori Osaki 1,  Takafumi Miyamoto 1,  Motohiro Sekiya 1,  Hirohito Sone 7,  Naoya Yahagi 6,  Yoshimi Nakagawa 8,  Satoshi Nitta 3,  Shuya Kandori 3,  Takahiro Kojima 9,  Chiaki Takahashi 4,  Hiroyuki Nishiyama 3,  Hitoshi Shimano 10
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
  • 2 Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: t-matsuz@md.tsukuba.ac.jp.
  • 3 Department of Urology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
  • 4 Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
  • 5 Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan.
  • 7 Department of Hematology, Endocrinology and Metabolism, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
  • 8 Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 9 Department of Urology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.
  • 10 Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8572, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: hshimano@md.tsukuba.ac.jp.
PMID: 40835210 DOI: 10.1016/j.bbadis.2025.168023
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.

Keywords

Bladder cancer (BC); ELOVL fatty acid elongase 6 (ELOVL6); Extracellular matrix (ECM); Fibroblast growth factor receptor 3 (FGFR3); Mitochondrial oxidative phosphorylation (OXPHOS).

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