Combined Transcriptomic and Epitranscriptomic Profiling Identifies THBS1 as A Regulator of Enzalutamide Resistance in...

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Cancer drug resistance involves adaptive transcriptional programs.
• N6-methyladenosine (m⁶A) RNA modification regulates mRNA processing and impacts cell fate.
• Prostate cancer (PC) resistance to enzalutamide (ARPI) is linked to androgen receptor (AR) alterations.

Purpose of the Study:

• To investigate the role of m⁶A modifications in the transition to enzalutamide resistance in PC.
• To identify specific transcripts affected by m⁶A modifications during resistance development.

Main Methods:

• Utilized methyl-RNA-immunoprecipitation followed by sequencing (MeRIP-seq) and RNA-seq.
• Compared m⁶A profiles and gene expression between enzalutamide-sensitive and resistant PC cells.
• Prioritized candidate genes using bioinformatics tools (GO, GSEA, TCGA, ORIEN).

Main Results:

• Identified 487 differentially methylated and expressed transcripts.
• Validated six top candidates, including THBS1, showing increased m⁶A and decreased transcript levels in resistant cells.
• siRNA-knockdown of THBS1 in sensitive cells induced enzalutamide resistance.

Conclusions:

• m⁶A modifications play a significant role in the development of enzalutamide resistance in PC.
• Downregulation of THBS1 directly contributes to rapid enzalutamide resistance.
• THBS1 is a potential driver of acute resistance in prostate cancer, representing a novel therapeutic target.