In a groundbreaking study poised to transform the therapeutic landscape of colorectal cancer, researchers have unveiled the critical role of the m^6A RNA demethylase ALKBH5 in maintaining cancer stemness and chemoresistance. This discovery offers promising avenues for interventions aimed at eradicating malignancies notorious for treatment evasion and relapse. The findings, recently published in Nature Communications by Zhou, Chen, Liu, and colleagues, illuminate the molecular underpinnings by which m^6A modifications dictate tumor aggressiveness and resilience.
Colorectal cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the recurrent failure of chemotherapy. The persistence of cancer stem cells (CSCs) within tumors is widely implicated as a culprit in chemoresistance and disease relapse. These CSCs possess self-renewal properties, allowing them to withstand cytotoxic insults and regenerate malignant growths even after aggressive chemotherapy. However, targeting these cells has been complicated by limited knowledge of the molecular mechanisms regulating their stemness and survival pathways.
At the heart of this investigation lies ALKBH5, an RNA demethylase enzyme known to reverse N6-methyladenosine (m^6A) modifications on mRNA transcripts. The m^6A mark is a widespread epitranscriptomic modification that dynamically tunes RNA stability, splicing, export, and translation. While the addition of m^6A marks has been extensively studied, less is understood about the functional consequences of their removal by erasers like ALKBH5 in the context of cancer biology.
The team employed state-of-the-art transcriptomic profiling and epitranscriptomic mapping to delineate the influence of ALKBH5 on colorectal cancer cells. They discovered that ALKBH5 expression is significantly upregulated in CRC stem cell populations, enabling the erasure of critical m^6A marks that stabilize oncogenic transcripts governing stemness. By demethylating these RNAs, ALKBH5 enhances their stability and translation, thereby sustaining the robust self-renewal capacities and drug resistance mechanisms of CSCs.
Functional validations were conducted using CRISPR-Cas9 mediated gene editing, which demonstrated that knocking out ALKBH5 severely impaired the formation and maintenance of colorectal CSCs. This depletion diminished their ability to form spheroids in vitro, a hallmark of stemness, and sensitized these cells to common chemotherapeutic agents such as 5-fluorouracil and oxaliplatin. Such observations underscore ALKBH5 as a linchpin in the molecular circuitry fostering tumor persistence under chemotherapeutic stress.
Delving deeper, the researchers identified key downstream mRNA targets modulated by ALKBH5-mediated m^6A demethylation. Transcripts encoding regulators of cell cycle progression, DNA repair, and anti-apoptotic pathways were found to be stabilized upon ALKBH5 activity, cumulatively enhancing CSC fitness and survival. Intriguingly, the abrogation of ALKBH5 disrupted these oncogenic transcriptome programs, highlighting its potential as a therapeutic target that strikes at the root of colorectal cancer recurrence.
The implications of this research are profound. Unlike previous therapeutic strategies focused largely on surface markers or signaling pathways, targeting the epitranscriptomic landscape opens a novel and promising avenue for combating tough-to-treat cancers. By pharmacologically inhibiting ALKBH5, it may be possible to simultaneously blunt CSC-driven tumor progression and resensitize tumors to chemotherapy, overcoming one of oncology’s most intractable challenges.
Moreover, the study underscores the complexity and adaptability of cancer cells that exploit epigenetic and epitranscriptomic mechanisms to survive therapy. ALKBH5’s role in the dynamic RNA methylation landscape reveals a previously underappreciated layer of regulation that cancer cells hijack. This not only advances our fundamental understanding of tumor biology but also predicates future research to explore epitranscriptomic modulators across different cancer types.
Importantly, this research paves the way for developing ALKBH5 inhibitors as adjunct therapeutic agents. Given the specificity of ALKBH5 in erasing m^6A marks, targeting this enzyme holds the promise of minimal off-target effects compared to traditional chemotherapy. Early-stage compounds identified through high-throughput screens have demonstrated feasibility, though extensive preclinical and clinical validations are necessary.
The translational potential of targeting ALKBH5 is further bolstered by the identification of biomarkers that predict patient response to ALKBH5-targeted therapies. Elevated ALKBH5 expression correlates with poor prognosis and high CSC burden in colorectal cancer patients, suggesting that stratifying patients based on ALKBH5 levels could optimize therapeutic outcomes.
On a broader scale, this study catalyzes a paradigm shift in precision oncology, emphasizing the importance of the RNA modification landscape alongside genetic and proteomic targets. The interplay between m^6A methylation and cancer pathogenicity beckons a new class of epitranscriptomic therapies that might complement existing immunotherapies and chemotherapies, potentially yielding synergistic effects.
Future directions inspired by this work include the exploration of ALKBH5’s interactions with other m^6A regulators such as METTL3 and FTO, as well as its influence on the tumor microenvironment. Investigating how ALKBH5 modulation affects immune cell infiltration, angiogenesis, and metastatic dissemination will be crucial to fully harness its therapeutic potential.
In conclusion, the targeting of the m^6A RNA demethylase ALKBH5 emerges as an innovative and effective means to undermine colorectal cancer stemness and chemoresistance. By disrupting the epitranscriptomic sustainment of CSCs, this approach offers hope for improved treatment responses and durable remission in a disease that has defied many prior interventions. The study by Zhou, Chen, Liu, and their team marks a significant leap forward in cancer research, heralding a new epoch where RNA methylation dynamics become viable targets in the fight against cancer.
Subject of Research: Targeting the m^6A eraser ALKBH5 to suppress colorectal cancer stemness and chemoresistance.
Article Title: Targeting of the m^6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.
Article References: Zhou, H., Chen, H., Liu, W. et al. Targeting of the m^6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67502-0
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