The Functional Role and Regulatory Mechanism of FTO m6A RNA Demethylase in Human Uterine Leiomyosarcoma

by Selleckchem | Oct 08 2023

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m6A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer.

Comments:

The study you mentioned focuses on investigating the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uterine leiomyosarcoma (uLMS), which is a subtype of uterine sarcoma associated with poor prognosis, high recurrence rates, and metastasis.

The researchers performed immunohistochemistry analysis and found that the levels of RNA demethylases FTO and ALKBH5 were abnormally upregulated in uLMS tissues compared to the adjacent myometrium. This suggests that dysregulation of m6A RNA methylation might play a role in uLMS development. The significance of these findings was determined using histochemical scoring assessment.

To further investigate the impact of FTO demethylase on uLMS, the researchers utilized a small, potent inhibitor called Dac51 to inhibit FTO activity. They found that inhibiting FTO with Dac51 resulted in a dose-dependent decrease in uLMS cell proliferation by inducing cell cycle arrest. RNA-seq analysis revealed that FTO inhibition led to a significant decrease in the expression of cell-cycle-related genes, including several CDK members, and an increase in the expression of CDKN1A, which is known to inhibit cell proliferation.

Furthermore, the researchers observed that Dac51 treatment caused the rewiring of several critical pathways involved in uLMS, such as TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling. These pathway alterations contributed to the suppression of the uLMS phenotype.

Transcription factor (TF) analyses indicated that epitranscriptional alterations induced by Dac51 might modulate cell cycle-related gene expression through TF-driven pathways and epigenetic networks in uLMS cells. This suggests that the intersection of RNA methylation and other epigenetic controls and pathways plays a role in uLMS pathogenesis.

Overall, the findings of this study suggest that targeting the dysregulated epitranscriptome, specifically RNA methylation machinery, could be a promising and novel strategy for treating uLMS. By inhibiting FTO demethylase, it was possible to suppress uLMS cell proliferation and modulate key signaling pathways associated with the disease. This approach provides a new perspective for understanding and potentially treating this aggressive uterine cancer.