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.
Highlights
During cancer, a major challenge faced by oncologists is the treatment of metastasis; a leading cause of cancer-related deaths around the world
After the tumor cells detached themselves from the primary tumor and the E.C.M. (2): a condition that results in different signaling from the primary tumor microenvironment due to its arrival at a secondary having a differential E.C.M. composition
We primarily focused on exploring the expression of histone methyltransferases, namely EZH2, EHMT1, EHMT2, DOT1L, ARID1A, and CARM1, that are well associated with primary tumorigenesis and distant metastasis in a wide variety of c ancers[17,18,19,20,21,22]
Summary
A major challenge faced by oncologists is the treatment of metastasis; a leading cause of cancer-related deaths around the world. A specialized cell death program, primarily occurs during the loss of contact of epithelial cells with the cell-extracellular matrix (E.C.M.). At the start of the anoikis program, major morphological changes i.e. activation, conformational changes, and dimerization of ligands of the cell surface lead towards the start of a series of molecular events mainly leading towards cell d eath[8]. This cell death can be either mitochondrial-mediated apoptosis signaling (intrinsic) or caspase-8-mediated apoptosis signaling (extrinsic). Since there is a difference in the E.C.M. composition between the secondary and the primary tumor sites and following the last step of metastasis, these metastasis cells must bypass anoikis
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