Feedback regulation between histone H3 lysine 18 lactylation and TROP2‐mediated glycolysis drives metastatic progression of colorectal cancer

TL;DR

The study reveals a feedback loop between histone lactylation and TROP2 signaling that drives colorectal cancer metastasis and suggests a new treatment approach using acriflavine.

Contribution

Discovery of a self-reinforcing H3K18 lactylation-TROP2 feedback loop in CRC metastasis and its disruption as a therapeutic strategy.

Findings

TROP2 promotes lactate production via YBX1-HIF-1α signaling, which increases H3K18 lactylation.

H3K18 lactylation enhances expression of metastasis-promoting genes and sustains TROP2 levels.

Acriflavine inhibits H3K18 lactylation and suppresses TROP2-driven metastasis in preclinical models.

Abstract

TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti‐TROP2 antibody‐drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.

Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2‐mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell‐derived xenograft (CDX), intra‐splenic injection models, and patient‐derived xenografts (PDX) validated TROP2 or TROP2‐induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome‐wide H3K18la profiling was performed by ChIP‐seq.

Here, we identify a self‐reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post‐therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1‐HIF‐1α signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2‐driven CRLM colonisation and progression. Mechanistically, ChIP‐seq detection reveals H3K18la deposition at a set of pro‐metastatic gene promoters, promoting their expression. Crucially, TROP2‐induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF‐1α inhibition with acriflavine, an old FDA‐approved agent, suppresses TROP2‐high CRLM progression in multiple pre‐clinical models.

Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2‐mediated CRLM progression and propose that disrupting the H3K18la–TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.

H3K18la is specifically increased in CRC cells in response to TROP2 signalling and drives TROP2‐mediated CRLM progressionGenome‐wide analysis shows H3K18la deposition at the promoters of metastasis‐promoting genes drives their expression in TROP2‐high CRC.Lactate sustains TROP2 expression in CRC cells via H3K18laAcriflavine suppresses TROP2‐driven CRLM by targeting the H3K18la/TROP2 feedback loop

H3K18la is specifically increased in CRC cells in response to TROP2 signalling and drives TROP2‐mediated CRLM progression

Genome‐wide analysis shows H3K18la deposition at the promoters of metastasis‐promoting genes drives their expression in TROP2‐high CRC.

Lactate sustains TROP2 expression in CRC cells via H3K18la

Acriflavine suppresses TROP2‐driven CRLM by targeting the H3K18la/TROP2 feedback loop

TROP2 is upregulated in CRC metastasis and promotes lactate overproduction via YBX1‐HIF‐1α signalling.TROP2 signalling induces H3K18la at metastasis genes promoters in CRC and promotes their expression.AccLactate sustains TROP2 expression in CRC cells via H3K18laAcriflavine suppresses TROP2‐driven CRLM by targeting the H3K18la/TROP2 feedback loop

TROP2 is upregulated in CRC metastasis and promotes lactate overproduction via YBX1‐HIF‐1α signalling.

TROP2 signalling induces H3K18la at metastasis genes promoters in CRC and promotes their expression.

AccLactate sustains TROP2 expression in CRC cells via H3K18la

Acriflavine suppresses TROP2‐driven CRLM by targeting the H3K18la/TROP2 feedback loop

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