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Function of the METTL3-NUP93 complex-mediated nuclear export of m6A-modified mRNAs in castration-resistant prostate cancer.

Award Number: R01CA279681
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Function of the METTL3-NUP93 complex-mediated nuclear export of m6A-modified mRNAs in castration-resistant prostate cancer. - PROJECT SUMMARY/ABSTRACT Misregulation of nucleoporins (NUPs), the essential constituents of nuclear pore complexes (NPCs), and dysfunction of N6-methyladenosine (m6A) signaling have been individually linked to cancer. Although it has been reported that NPC-mediated macromolecular transport cooperates with m6A modification to control movement of messenger RNAs (mRNAs) out of the nucleus, contribution of such cooperation to pathogenesis and progression of cancer remains obscure. Our proteomic study of NPC-associated cofactors revealed a direct interaction between the m6A methyltransferase METTL3 and one of the NUP proteins called NUP93 in several cancer cell lines including prostate cancer (PCa). Although each protein has been indicated to involve in the progression of some types of human malignancies, their functions and molecular mechanisms of action are poorly understood in PCa, let alone their interaction. Our immunohistochemistry analysis showed that both METTL3 and NUP93 proteins are upregulated in metastatic, castration-resistant prostate cancer (CRPC), a lethal form of the disease, compared to primary tumors and their normal counterparts. Disrupting the METTL-NUP93 complex by genetic mutations of residues mediating this interaction abrogated proliferation and migration of CRPC cells. These results suggest that the METTL3-NUP93 complex may play an important role in PCa progression to castration resistance and the underlying mechanism is worthy of further investigation. Considering that both NPCs and m6A machinery control the nucleocytoplasmic transport of mRNAs, we performed fractionation RNA-seq to identify mRNA molecules whose nuclear abundance is changed upon knockdown of METTL3 and NUP93 in PCa cells. A large group of mRNAs were significantly retained in the nuclei of both knockdown cells, suggesting that METTL3 and NUP93 coregulate the nuclear export of these mRNAs. The mRNA cargos of the METTL3-NUP93 complex are preferentially methylated, allowing them to be selected by the complex via association with METTL3. Interestingly, a subset of these mRNA cargos is functionally involved in the biosynthesis of the sex hormone androgen that is well known to activate the main driver of PCa progression, androgen receptor (AR). Indeed, overexpression of the wild-type METTL3 and NUP93, but not the mutant forms interrupting the new mRNA transport pathway, increases intracellular androgen levels in PCa cells, upregulates the expression of AR target genes even without addition of the ligand and confers the androgen- independent growth of PCa cells, implying the development of hormone-refractory phenotypes. All these effects can be alleviated by the pharmacological inhibitors of the steroidogenic enzymes encoded by the target mRNAs of the METTL3-NUP93 complex. So, our hypothesis is: Upregulation of METTL3 and NUP93 promotes PCa progression by facilitating the nuclear export of mRNAs, a subgroup of which encode androgen biosynthesis enzymes that trigger the activation of AR signaling in CRPC. In this proposal, we will address three mechanistically and clinically important questions in the fields of RNA methylation and cancer biology: (1). How the METTL3-NUP93 complex selects target mRNAs and expediates their nuclear export; (2). How the mRNA export mediated by the METTL3-NUP93 complex orchestrates AR activity under castration condition; (3). How we can genetically and pharmacologically block the new mRNA transport pathway to treat CRPC. We will leverage our experience in genome/transcriptome-wide profiling and m6A-editing tools, as well as that of our collaborators in high-resolution microscopy and establishment of preclinical models, to elucidate the function of crosstalk between NPCs and m6A machinery in cancer and to explore the mechanisms underlying the development of CRPC using cellular and animal models.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $382,418 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	3	1/7/2026	NON-COMPETING CONTINUATION	$382,418
														Subtotal = $382,418

Issue Date FY: 2025 ( Subtotal = $412,955 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	2	2/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$412,955
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	1	3/18/2025	NEW	$0
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	1	2/14/2025	NEW	$0
														Subtotal = $412,955

Issue Date FY: 2024 ( Subtotal = $439,997 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	1	11/27/2023	NEW	$439,997
														Subtotal = $439,997

Grand Total All Awards = $1,235,370

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Function of the METTL3-NUP93 complex-mediated nuclear export of m6A-modified mRNAs in castration-resistant prostate cancer.

Award Number: R01CA279681

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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