m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression
Both nuclear pore complexes (NPCs) and RNA N6-methyladenosine (m6A) machinery are indispensable for proper cellular function. Although their collaborative roles in the nuclear export of messenger RNAs (mRNAs) have been reported, it remains ambiguous whether and how this collaboration may contribute to cancer progression. Here we identify a functional cooperation between NPCs and m6A signaling…
Researchers have discovered a connection between nuclear pore complexes and m6A signaling that contributes to the progression of castration-resistant prostate cancer (CRPC). The study reveals that the nuclear export of m6A-modified mRNAs, facilitated by the interaction between RNA methyltransferase METTL3 and the nucleoporin NUP93, is linked to cholesterol biosynthesis.
Cholesterol is essential for the production of androgens within tumors, a key factor driving CRPC. The researchers found that overexpressing wild-type METTL3 or NUP93, but not dead or mutant versions, led to increased intracellular androgen levels. This in turn activated androgen receptor (AR) signaling even in castrate conditions and promoted the growth of prostate cancer cells both in laboratory settings and in living organisms.
Crucially, blocking METTL3 activity or demethylating mRNAs coding for cholesterol biosynthesis enzymes effectively suppressed CRPC malignancy. The findings suggest a potential therapeutic target - the m6A-METTL3-NUP93 axis - that connects nuclear mRNA export and metabolic reprogramming to fuel CRPC progression, offering a novel approach for treating this aggressive disease.
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