Aug 2026· Journal of Experimental & Clinical Cancer Research· 0 citations
Abstract
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.
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.
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.
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.
Functional assays demonstrated that WNT activation enhances tumor progression in immunocompetent settings, indicating immune evasion as a key driver of malignant progression.
M. Mastel, A. Guiseris Martinez, Umberto Pozza et al.· Gastroenterology· 0 citations
The study demonstrates that TFEB regulates the expression of the multidrug efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2), a crucial factor in drug resistance mechanisms, and targets TNKS represents a potentially effective therapeutic approach to address cisplatin resistance and improve treatment outcomes in TNBC.
Shariqa Jan, Kaneez Fatima, S. Khan et al.· Molecular Biology Reports· 0 citations
BACKGROUND
Metabolic reprogramming fuels colorectal cancer (CRC), yet upstream regulators that lock cells into a glycolytic state remain incompletely defined.
METHODS
We integrated single-cell and spatial transcriptomics with GWAS-eQTL-Mendelian randomization to nominate CRC-associated candidate genes, and profiled their expression, spatial localization, and prognostic value in patient cohorts. The function of MTFR1 was tested by proliferation, migration/invasion, EMT marker analysis, and Seahorse extracellular-flux assays. Mechanisms were interrogated using MeRIP-qPCR, mRNA stability, and dual-luciferase assays. In vivo relevance was evaluated in subcutaneous xenografts.
RESULTS
MTFR1 emerged as a CRC-associated gene whose high expression was associated with poorer overall and disease-free survival. MTFR1 silencing curtailed proliferation, migration and invasion, reversed EMT marker changes, reduced glycolytic rate and ATP output, and increased mitochondrial respiration. In mice, stable MTFR1 knockdown significantly restrained tumor growth. Mechanistically, METTL3 deposited m^6A on MTFR1 transcripts, while IGF2BP2 bound MTFR1 mRNA and enhanced its stability, thereby sustaining MTFR1 expression.
CONCLUSION
A METTL3-m^6A-IGF2BP2 axis maintains MTFR1 expression to drive glycolytic reprogramming and CRC progression. MTFR1 represents a prognostic biomarker and a potential therapeutic node linking epitranscriptomic regulation to metabolic adaptation in CRC.
Li-Qiang Wei, Deng-He Liu, Chun-Yu Lin et al.· Journal of Gastroenterology...· 0 citations
BACKGROUND
Colorectal cancer peritoneal metastasis (CRCPM) represents a highly aggressive clinical condition associated with limited therapeutic options and poor prognosis. Anoikis resistance, a specialized form of apoptosis induced by loss of cell-matrix interactions, is essential for tumor cell survival during peritoneal dissemination. However, the molecular mechanisms underlying anoikis resistance in CRCPM remain poorly understood.
METHODS
Differentially expressed lncRNAs associated with CRCPM were identified using microarray analysis and validated in clinical specimens. Gain- and loss-of-function assays were performed to evaluate the biological role of MIAT in colorectal cancer (CRC) cells, patient-derived organoids, and in vivo models. RNA pull-down, luciferase reporter, and RNA immunoprecipitation (RIP) assays were conducted to investigate the ceRNA mechanism. Methylated RNA immunoprecipitation (MeRIP) and RNA stability assays were used to assess m6A modification and its regulatory effects on MIAT.
RESULTS
MIAT was significantly upregulated in CRCPM tissues and anoikis-resistant CRC cells and was associated with poor prognosis. Functional assays demonstrated that MIAT silencing suppressed CRC cell proliferation, migration, invasion, and anoikis resistance in vitro and inhibited tumor growth and peritoneal metastasis in vivo. Mechanistically, MIAT acted as a competing endogenous RNA by sponging miR-181a-5p, thereby upregulating the anti-apoptotic protein MCL1. Furthermore, MIAT stability was enhanced by METTL3-mediated m6A modification in an IGF2BP2-dependent manner.
CONCLUSIONS
These findings identify a novel m6A-MIAT/miR-181a-5p/MCL1 signaling axis that promotes anoikis resistance and peritoneal metastasis in CRC. This study provides mechanistic insights into CRCPM progression and highlights MIAT as a potential prognostic biomarker and therapeutic target.
Lin Shu, Liu Yang, Yilin Yin et al.· International Immunopharmaco...· 0 citations
Introduction Despite advances in colorectal cancer (CRC) treatment, the chromosomal instability (CIN)-positive subgroup remains refractory to conventional therapies and immunotherapy. C2orf76, a poorly characterized gene identified as a CIN-linked candidate in CRC through bioinformatic analyses, has been associated with favorable prognosis and potential immune-related functions. However, its biological roles and underlying mechanisms in CRC remain largely unexplored. Methods To investigate the role of C2orf76, we generated knockout (KO), overexpression (OE), and rescue (RE) cell lines in CRC models. We performed RNA-seq, RT-qPCR, and Western blotting to examine transcriptomic and protein-level changes. Functional assays included proliferation, migration, cisplatin sensitivity, pyroptosis (GSDME cleavage), cytokinesis-block micronucleus assay (CBMN) for CIN, and γ-H2AX foci detection for DNA double-strand breaks. Results Unexpectedly, C2orf76 KO suppressed proliferation and migration, contradicting its favorable prognostic association and suggesting a complex regulatory role. RNA-seq revealed altered genes involved in chromosome segregation, cell cycle, platinum resistance, P53 signaling, and oncogenic pathways. RT-qPCR validated changes in chromosomal stability-related genes CDT1 and FOXM1, which were further verified by Western blotting. Further experiments showed that KO inhibited cisplatin-induced pyroptosis and cleavage of GSDME, whereas OE promoted migration and enhanced cisplatin sensitivity. The CBMN assay confirmed that C2orf76 significantly impacts chromosomal instability levels in CRC cells. C2orf76 KO cells also exhibited elevated γ-H2AX foci after cisplatin treatment. Rescue of C2orf76 expression reversed the KO-induced suppression of proliferation and migration, restored cisplatin sensitivity and pyroptosis, and reduced chromosomal instability. Discussion These findings unveil a context-dependent duality of C2orf76: knockout increases CIN, reduces proliferation and migration, but promotes chemoresistance; overexpression enhances cisplatin-induced pyroptosis and drug sensitivity yet increases migration. Thus, C2orf76 establishes a functional link between CIN, cell death, and therapeutic response, positioning it as a tunable target that may require context-dependent modulation for effective CRC intervention. This study not only characterizes a previously understudied gene but also provides a mechanistic framework for understanding how CIN-associated genes can exert opposing effects on tumor progression and treatment outcome.
Li Zhang, Zhu Song, Pin-Jie Zhang et al.· Frontiers in Oncology· 0 citations
A role for p16 loss as a candidate functional driver of ICI resistance associated with 9p21 loss in TNBC-BM is suggested and warrant further investigation given the need to nominate biomarkers for ICI response to inform patient care.
Varun Sasisekharan, Naema Nayyar, C. Torrini et al.· Neuro-Oncology Advances· 0 citations
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