m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression

Abstract

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 that promotes the development of castration-resistant prostate cancer (CRPC). We showed that nuclear export of m6A-modified mRNAs, mediated by the interaction between RNA methyltransferase METTL3 and the nucleoporin NUP93, is functionally coupled to cholesterol biosynthesis. Given that cholesterol-fueled intratumoral androgen production is one of the mechanisms driving CRPC, we demonstrated that overexpression of the wild-type METTL3 or NUP93, but neither the enzymatically dead METTL3 nor the mutant NUP93 that loses METTL3-interacting capability, elevates intracellular levels of androgens, activates AR signaling under castrate condition, and promotes androgen-independent growth of prostate cancer cells both in vitro and in vivo. Importantly, pharmacological inhibition of METTL3 or targeted demethylation on mRNAs encoding key cholesterol biosynthesis enzymes effectively suppressed CRPC malignancy. Together, these findings uncover a therapeutically targetable m6A-METTL3-NUP93 axis that links nuclear mRNA export and metabolic reprogramming to fuel CRPC progression, providing a conceptually new strategy for the treatment of this lethal disease.

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BibTeX RIS

BibTeX

@misc{lee2026m6adriven,
  title = {{m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression}},
  author = {J. H. Lee and Z. Zhang and J. Hong and J.-H. Jeong and H. Ye and D. Srinivasan and L. Kang and S. Lamichhane and N. Amselle and K. A. John and M. T. Hinds and A. N. Agarwal and D. M. Lee and S. Han and M. P. Roudier and H.-M. Lam and E. Corey and K. Xu},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.24.753979},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753979v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression
AU  - J. H. Lee
AU  - Z. Zhang
AU  - J. Hong
AU  - J.-H. Jeong
AU  - H. Ye
AU  - D. Srinivasan
AU  - L. Kang
AU  - S. Lamichhane
AU  - N. Amselle
AU  - K. A. John
AU  - M. T. Hinds
AU  - A. N. Agarwal
AU  - D. M. Lee
AU  - S. Han
AU  - M. P. Roudier
AU  - H.-M. Lam
AU  - E. Corey
AU  - K. Xu
PY  - 2026
DA  - 2026/09/24
PB  - bioRxiv
DO  - 10.64898/2026.09.24.753979
UR  - https://www.biorxiv.org/content/10.64898/2026.09.24.753979v1
AB  - 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 that promotes the development of castration-resistant prostate cancer (CRPC). We showed that nuclear export of m6A-modified mRNAs, mediated by the interaction between RNA methyltransferase METTL3 and the nucleoporin NUP93, is functionally coupled to cholesterol biosynthesis. Given that cholesterol-fueled intratumoral androgen production is one of the mechanisms driving CRPC, we demonstrated that overexpression of the wild-type METTL3 or NUP93, but neither the enzymatically dead METTL3 nor the mutant NUP93 that loses METTL3-interacting capability, elevates intracellular levels of androgens, activates AR signaling under castrate condition, and promotes androgen-independent growth of prostate cancer cells both in vitro and in vivo. Importantly, pharmacological inhibition of METTL3 or targeted demethylation on mRNAs encoding key cholesterol biosynthesis enzymes effectively suppressed CRPC malignancy. Together, these findings uncover a therapeutically targetable m6A-METTL3-NUP93 axis that links nuclear mRNA export and metabolic reprogramming to fuel CRPC progression, providing a conceptually new strategy for the treatment of this lethal disease.
ER  -

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