Emerging role of G9a in cancer stemness and promises as a therapeutic target

The histone methyltransferase G9a is well-documented for its implication in neoplastic growth. However, recent investigations have demonstrated a key involvement of this chromatin writer in maintaining the self-renewal and tumor-initiating capacities of cancer stem cells (CSCs). Direct inhibition of G9a's catalytic activity was reported as a promising therapeutic target in multiple preclinical studies. Yet, none of the available pharmacological inhibitors of G9a activity have shown success at the early stages of clinical testing. Here, we discuss central findings of oncogenic expression and activation of G9a in CSCs from different origins, as well as the impact of the suppression of G9a histone methyltransferase activity in such contexts. We will explore the challenges posed by direct and systemic inhibition of G9a activity in the perspective of clinical translation of documented small molecules. Finally, we will discuss recent advances in drug discovery as viable strategies to develop context-specific drugs, selectively targeting G9a in CSC populations.

Automated summary

G9a histone methyltransferase is known for its involvement in tumor growth, particularly in CSCs. While direct inhibition of its catalytic activity is a promising therapeutic target, available pharmacological inhibitors have not been successful in early clinical testing. This study discusses the oncogenic role of G9a in CSCs and the challenges of inhibiting its activity for clinical translation. Recent advances in drug discovery aim to develop context-specific drugs targeting G9a in CSC populations.