# SMYD3 synergises with RACK1 to promote colorectal cancer lung metastasis by recruiting SMAD3

## TL;DR

This study identifies a protein complex involving SMYD3 and RACK1 that promotes colorectal cancer metastasis to the lungs, suggesting a new therapeutic target.

## Contribution

The study reveals a novel tripartite interaction between SMYD3, RACK1, and SMAD3 that drives CRC metastasis.

## Key findings

- SMYD3 overexpression correlates with poor CRC prognosis and increased metastasis.
- RACK1 mediates SMYD3-SMAD3 complex formation to activate TSKU transcription.
- Disrupting the SMYD3-RACK1-SMAD3 axis may inhibit CRC metastasis.

## Abstract

Cancer metastasis is the leading cause of mortality associated with cancer, and the prognosis for patients diagnosed with colorectal cancer(CRC) largely depends on the occurrence of metastasis during the progression of the disease. A comprehensive understanding of the mechanisms underlying metastasis in CRC is essential for advancing treatment strategies. Through integrated bioinformatics analysis of mRNA expression profiles and epigenetic modifiers, we identified SMYD3 as the top differentially expressed histone modifier in CRC. Clinically, SMYD3 overexpression significantly associates with poor prognosis and enhances metastatic potential. Utilizing immunoprecipitation-mass spectrometry, we discovered RACK1 as a novel SMYD3-interacting protein. Subsequent mechanistic studies revealed a tripartite interaction network: SMYD3 recruits SMAD3 through RACK1-mediated scaffolding, facilitating transcriptional activation of the downstream effector TSKU. Notably, RACK1 depletion disrupts SMYD3-SMAD3 complex formation, establishing the critical role of this axis in metastasis regulation. Consequently, inhibiting the SMYD3-SMAD3 interaction may represent a promising therapeutic strategy for addressing CRC metastasis. In conclusion, targeting the SMYD3-RACK1-SMAD3 transcriptional complex presents a viable approach for the treatment of CRC metastasis.

The online version contains supplementary material available at 10.1186/s12964-026-02687-5.