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Updated: Nov 19, 2025
Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts
Published on: April 29, 2014
Molecular profiling of epigenetic landscape of cancer cells during extracellular matrix detachment
Mohammad Imran Khan1,2, Mazin A Zamzami3,4, Aftab Ahmad5
1Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia. mikhan@kau.edu.sa.
Abstract:
During cancer, a major challenge faced by oncologists is the treatment of metastasis; a leading cause of cancer-related deaths around the world. Metastasis involves a highly ordered sequence of events starting with the detachment of tumor cells from the extracellular matrix (E.C.M.). In normal cells, detachment from E.C.M. triggers programmed cell death, termed anoikis. However, tumor cells dodge their way to anoikis and spread to distant sites for initiating the metastatic program. In this work, we explored the impact of E.C.M. detachment on the expression of some major oncogenic histone methyltransferases. Results showed both EZH2 expression and its enzymatic activity were significantly increased in E.C.M. detached cancer cells when compared to the attached cells. Inhibition of EZH2 results in a significant reduction in cell proliferation, spheroids size, and induction in apoptosis in E.C.M. detached cells. Furthermore, we observed a reduction in EZH2 expression levels in single cells when compared to clusters of E.C.M. detached cells. Finally, we combined the EZH2 inhibition with AMPK, known to be highly expressed in E.C.M. detached cancer cells and observed antagonistic effects between the two pathways. The observed results clearly showed that E.C.M. detached cancer cells require oncogenic EZH2 and can be targeted by EZH2 inhibitors.
Insights
Cancer cells evade cell death upon detachment by increasing EZH2 expression. Inhibiting EZH2 reduces cancer cell proliferation and metastasis, offering a potential therapeutic target for advanced cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastasis is a leading cause of cancer mortality, driven by tumor cells evading anoikis (programmed cell death) after detaching from the extracellular matrix (E.C.M.).
- Understanding how cancer cells survive E.C.M. detachment is crucial for developing effective anti-metastasis therapies.
Purpose of the Study:
- To investigate the role of oncogenic histone methyltransferases, specifically EZH2, in cancer cells that have detached from the E.C.M.
- To evaluate the therapeutic potential of targeting EZH2 in E.C.M. detached cancer cells.
Main Methods:
- Analysis of EZH2 expression and enzymatic activity in E.C.M. detached versus attached cancer cells.
- Assessment of the effects of EZH2 inhibition on cell proliferation, spheroid formation, and apoptosis in detached cells.
- Investigation of the interaction between EZH2 inhibition and AMPK signaling in E.C.M. detached cells.
Main Results:
- EZH2 expression and activity were significantly elevated in E.C.M. detached cancer cells compared to attached cells.
- Inhibition of EZH2 markedly reduced proliferation and spheroid size while increasing apoptosis in detached cancer cells.
- E.C.M. detached cancer cells showed reduced EZH2 expression when single compared to clusters, and EZH2 inhibition demonstrated antagonistic effects with AMPK signaling.
Conclusions:
- E.C.M. detached cancer cells rely on oncogenic EZH2 for survival and proliferation.
- Targeting EZH2 with inhibitors presents a promising therapeutic strategy to combat cancer metastasis.
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