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Peer-reviewedCC BY 4.0Journal of Experimental & Clinical Cancer Research : CR

Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis

  • Yichao Hou1,2
  • Di Wu1,2
  • Yanyu Wei3
  • Bohui Yu1,2
  • Donghan Shao1,2
  • Dachun Cao1,2
  • Ping Wang1,2
  • Mei Guo1,2
  • Hang Yin1,2
  • Li Huo1,2
  • Wenjun Gu1,2
  • Yaping Liu1,2
2 more authors
  • Qingwei Zhang4
  • Dong Wang1,2
4 affiliations
  1. 1Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Digestive Disease Research and Clinical Translation Center, Department of Gastroenterology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, China
  2. 2Department of Gastroenterology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  3. 3Department of Oncology, East Hospital Affiliated to Tongji University, Tongji University School of Medicine, Tongji University, Shanghai, China
  4. 4Division of Gastroenterology and Hepatology, Key Laboratory Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 160 Pujian Road, Pudong New Area, Shanghai, China
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Abstract

Background: BRAF-mutant (BRAF-MT) colorectal cancer (CRC) represents a clinically aggressive subtype characterized by distinct biological features and significantly worse prognosis compared to BRAF wild-type (BRAF-WT) CRC, with median survival reduced by approximately 40%. The therapeutic resistance of BRAF-MT CRC stems primarily from BRAF-driven dysregulation of tumor cell proliferation. However, the molecular mechanisms underlying the aggressive phenotype and potential therapeutic vulnerabilities remain incompletely understood.

Methods: Bioinformatic analyses were employed to identify candidate genes. A combination of in vitro (cell proliferation, clonal formation), ex vivo (patient-derived and mouse intestinal organoids), and in vivo (xenograft models) assays were used to assess oncogenic function. Mechanistic investigations included Western blotting, qRT-PCR, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays to delineate the regulatory axis. Fatty acid metabolism and ferroptosis were evaluated by a combination of metabolomic, biochemical, and cellular assays.

Results: Bioinformatic screening identified ankyrin repeat domain 54 (ANKRD54) as selectively overexpressed in BRAF-MT CRC and significantly associated with adverse prognosis. Inhibition of ANKRD54 markedly suppressed clonogenic potential, cellular proliferation in vitro, organoid formation in both PDOs and cKI mouse-derived organoids, and tumor growth in vivo. Mechanistically, lysine acetyltransferase 2 A (KAT2A) promoted ANKRD54 transcriptional activation through H3K27 acetylation. ANKRD54 subsequently formed a functional complex with CCAAT/enhancer binding protein beta (CEBPB), cooperatively inducing ELOVL fatty acid elongase 6 (ELOVL6) expression. This KAT2A-mediated ANKRD54/CEBPB/ELOVL6 transcriptional axis reprogrammed fatty acid metabolism, selectively suppressing ferroptosis in BRAF-MT CRC. Pharmacological targeting of either ANKRD54 or ELOVL6 substantially enhanced the therapeutic efficacy of Vemurafenib-based treatment in BRAF-MT CRC models. Clinical data corroborated that elevated ANKRD54 expression promoted malignant progression and predicted poor outcomes through this ELOVL6-dependent metabolic pathway.

Conclusions: This study elucidates a novel KAT2A-mediated ANKRD54/CEBPB/ELOVL6 axis driving aggressive tumor behavior through regulating fatty acid metabolic and ferroptosis evasion. These findings establish ANKRD54 and ELOVL6 as promising therapeutic targets for combination strategies to overcome therapeutic resistance in BRAF-MT CRC patients.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13046-026-03809-0.

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Cite

BibTeXRIS
BibTeX
@article{hou2026targeting,
  title = {{Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis}},
  author = {Yichao Hou and Di Wu and Yanyu Wei and Bohui Yu and Donghan Shao and Dachun Cao and Ping Wang and Mei Guo and Hang Yin and Li Huo and Wenjun Gu and Yaping Liu and Qingwei Zhang and Dong Wang},
  journal = {Journal of Experimental \& Clinical Cancer Research : CR},
  year = {2026},
  month = aug,
  doi = {10.1186/s13046-026-03809-0},
  url = {https://doi.org/10.1186/s13046-026-03809-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis
AU  - Yichao Hou
AU  - Di Wu
AU  - Yanyu Wei
AU  - Bohui Yu
AU  - Donghan Shao
AU  - Dachun Cao
AU  - Ping Wang
AU  - Mei Guo
AU  - Hang Yin
AU  - Li Huo
AU  - Wenjun Gu
AU  - Yaping Liu
AU  - Qingwei Zhang
AU  - Dong Wang
PY  - 2026
DA  - 2026/08/11
JO  - Journal of Experimental & Clinical Cancer Research : CR
DO  - 10.1186/s13046-026-03809-0
UR  - https://doi.org/10.1186/s13046-026-03809-0
AB  - Background: BRAF-mutant (BRAF-MT) colorectal cancer (CRC) represents a clinically aggressive subtype characterized by distinct biological features and significantly worse prognosis compared to BRAF wild-type (BRAF-WT) CRC, with median survival reduced by approximately 40%. The therapeutic resistance of BRAF-MT CRC stems primarily from BRAF-driven dysregulation of tumor cell proliferation. However, the molecular mechanisms underlying the aggressive phenotype and potential therapeutic vulnerabilities remain incompletely understood.  Methods: Bioinformatic analyses were employed to identify candidate genes. A combination of in vitro (cell proliferation, clonal formation), ex vivo (patient-derived and mouse intestinal organoids), and in vivo (xenograft models) assays were used to assess oncogenic function. Mechanistic investigations included Western blotting, qRT-PCR, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays to delineate the regulatory axis. Fatty acid metabolism and ferroptosis were evaluated by a combination of metabolomic, biochemical, and cellular assays.  Results: Bioinformatic screening identified ankyrin repeat domain 54 (ANKRD54) as selectively overexpressed in BRAF-MT CRC and significantly associated with adverse prognosis. Inhibition of ANKRD54 markedly suppressed clonogenic potential, cellular proliferation in vitro, organoid formation in both PDOs and cKI mouse-derived organoids, and tumor growth in vivo. Mechanistically, lysine acetyltransferase 2 A (KAT2A) promoted ANKRD54 transcriptional activation through H3K27 acetylation. ANKRD54 subsequently formed a functional complex with CCAAT/enhancer binding protein beta (CEBPB), cooperatively inducing ELOVL fatty acid elongase 6 (ELOVL6) expression. This KAT2A-mediated ANKRD54/CEBPB/ELOVL6 transcriptional axis reprogrammed fatty acid metabolism, selectively suppressing ferroptosis in BRAF-MT CRC. Pharmacological targeting of either ANKRD54 or ELOVL6 substantially enhanced the therapeutic efficacy of Vemurafenib-based treatment in BRAF-MT CRC models. Clinical data corroborated that elevated ANKRD54 expression promoted malignant progression and predicted poor outcomes through this ELOVL6-dependent metabolic pathway.  Conclusions: This study elucidates a novel KAT2A-mediated ANKRD54/CEBPB/ELOVL6 axis driving aggressive tumor behavior through regulating fatty acid metabolic and ferroptosis evasion. These findings establish ANKRD54 and ELOVL6 as promising therapeutic targets for combination strategies to overcome therapeutic resistance in BRAF-MT CRC patients.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13046-026-03809-0.
SN  - 0392-9078
SN  - 1756-9966
ER  -