ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Prostate cancer (PCa) frequently progresses to castration-resistant PCa (CRPC).
• Docetaxel (DTX) resistance is a significant challenge in CRPC treatment.
• The role of RNA modification enzymes in CRPC progression and drug resistance is an emerging area of research.

Purpose of the Study:

• To investigate the function of the N6-methyladenosine (m6A) demethylase ALKBH5 in the development of DTX resistance in CRPC.
• To elucidate the molecular mechanism by which ALKBH5 influences DTX resistance.

Main Methods:

• Analysis of ALKBH5 expression in CRPC clinical samples.
• In vitro functional studies involving ALKBH5 overexpression and knockdown in PCa cells.
• Investigation of the m6A reader IGF2BP2 and its role in DTX resistance.
• Multi-omics analysis to identify downstream targets of ALKBH5.
• Validation in clinical samples and organoid models.

Main Results:

• ALKBH5 expression was significantly decreased in CRPC samples.
• ALKBH5 overexpression inhibited PCa cell proliferation and migration, while knockdown enhanced these effects and increased DTX resistance.
• Knockdown of the m6A reader IGF2BP2 reversed DTX resistance.
• CLSPN, a DNA replication stress regulator, was identified as a key downstream target.
• ALKBH5 demethylation of CLSPN mRNA reduces its stability in an IGF2BP2-dependent manner, leading to DTX resistance.

Conclusions:

• The ALKBH5-IGF2BP2 axis plays a critical role in modulating DTX resistance in metastatic CRPC.
• This modulation occurs via m6A-dependent regulation of CLSPN mRNA stability.
• Targeting the ALKBH5-IGF2BP2-CLSPN pathway presents a potential therapeutic strategy to overcome DTX resistance in CRPC.