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Updated: Sep 17, 2025

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Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis

Martina Lepore Signorile1, Elisabetta Di Nicola1, Giovanna Forte1

  • 1Medical Genetics, National Institute of Gastroenterology, IRCCS "Saverio de Bellis" Research Hospital, Castellana Grotte, BA, Italy.

Signal Transduction and Targeted Therapy
|June 30, 2025
PubMed

Insights

Targeting SMYD3, a key protein in colorectal cancer stem cells (CSCs), inhibits tumor growth and metastasis by affecting c-MYC activity. This offers a new therapeutic strategy for colorectal cancer (CRC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Colorectal cancer (CRC) stem cells (CSCs) drive chemoresistance, recurrence, and metastasis.
  • Identifying molecular targets is crucial for effective CRC treatment.
  • SMYD3's role in CRC stem cell biology requires further elucidation.

Purpose of the Study:

  • To investigate the role of SET and MYND Domain Containing 3 (SMYD3) in colorectal cancer stem cell (CRC-SC) biology.
  • To determine if SMYD3 is a viable therapeutic target for colorectal cancer.

Main Methods:

  • In vitro and in vivo molecular and functional characterization of SMYD3 in CRC-SCs.
  • Analysis of SMYD3's interaction with and methylation of c-MYC.
  • Assessment of SMYD3 inhibition/ablation effects on CRC-SC self-renewal, clonogenic potential, tumorigenicity, and metastasis.

Main Results:

  • SMYD3 directly interacts with and methylates c-MYC, modulating its transcriptional activity related to stemness.
  • Pharmacological inhibition or genetic ablation of SMYD3 reduces CRC-SC clonogenic and self-renewal potential.
  • SMYD3 inhibition/ablation significantly decreases CRC tumorigenicity and metastatic potential in vivo.

Conclusions:

  • SMYD3 plays a pivotal role in colorectal cancer stem cell proliferation and metastasis.
  • SMYD3 acts on c-MYC to promote stemness and malignancy in CRC.
  • SMYD3 is a promising therapeutic target for overcoming CRC chemoresistance and metastasis.

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