Abstract 5593: METTL3-NUP93 axis as a novel therapeutic target in castration-resistant prostate cancer (CRPC)

Abstract Androgens and androgen receptor (AR) are the key factors driving the development and progression of prostate cancer. Extensive studies confirm both androgens and AR are required for normal growth and development of the prostate gland, and also in prostate cancer pathogenesis and androgen-independent cancer progression. Therefore, androgen deprivation therapies or targeting AR function have always been the mainstay of therapeutic strategy against advanced prostate cancers. However, the current therapeutic strategies are temporally effective in suppressing prostate tumors, and eventually develop metastatic disease. Nuclear pore complex (NPC) is a large complex composed of approximately 30 different proteins termed nucleoporins (NUPs), which serve as the structural and functional units for macromolecules shuttling including proteins and messenger RNAs (mRNAs) between nucleus and cytoplasm. Abnormal expression or genetic alterations of NUP genes has been indicated to involve in the progression of prostate cancer, but the underlying molecular mechanisms are poorly understood. We recently found that the m6A methyltransferase METTL3 directly interacts with nucleoporin 93 (NUP93), one of the NPC components in multiple prostate cancer cells, which seems to be more robust in the castration-resistant prostate cancer (CRPC) cell lines. Disruption of METTL3-NUP93 axis abrogated proliferation and oncogenic phenotypes of CRPC cells, suggesting that the METTL3-NUP93 axis may play an important role in prostate cancer progression to castration resistance. Most importantly, a subgroup of mRNAs regulated through METTL3-NUP93 axis encode cholesterol biosynthesis enzymes that trigger the activation of persistent AR signaling in CRPC. Therefore, Our current findings suggest that inhibition of METTL3-NUP93 axis may represent a promising therapeutic strategy for CRPC, the lethal form of the disease. Citation Format: Jihoon Lee, Zhao Zhang, Juyeong Hong, Kexin Xu. METTL3-NUP93 axis as a novel therapeutic target in castration-resistant prostate cancer (CRPC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5593.