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ATAT1-Driven Acetylation as a Mechanism for IMPDH2 Regulation in Melanoma

Award Number: F31CA317823
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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ATAT1-Driven Acetylation as a Mechanism for IMPDH2 Regulation in Melanoma - ABSTRACT Metastatic melanoma is the deadliest form of skin cancer, and its incidence rate is increasing. Despite recent advances in cancer therapy, metastatic melanoma remains an incurable disease. Melanoma cell acquisition of invasive phenotypes is crucial for the progression of localized to metastatic melanoma. Therefore, further investigation into the molecular mechanisms that drive and sustain melanoma cell invasion and metastasis is necessary. Melanoma cell invasion depends on the activation of RHO-GTPases, a family of G- proteins that become active upon binding to guanosine triphosphate (GTP). Dysregulation of G-proteins, including RHO-GTPases, contributes to oncogenesis by promoting cell protrusion formation and migration. Historically, fluctuations in intracellular GTP levels were not considered to influence G-protein activity. However, total intracellular GTP levels alone do not reveal variations in local levels of free GTP that affect the activity of G-proteins in subcellular locations. Using novel genetically encoded internally normalized intracellular biosensors generated in our lab, we previously reported that gradients of free GTP exist within melanoma cells, and activation of the RHO-GTPase, RAC1, is dependent on the local availability of free GTP. Our prior work identified inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme that catalyzes de novo GTP synthesis, as a key regulator of local GTP production in cancer cell protrusions. Furthermore, we showed that disruption of IMPDH2 and RAC1 interactions decreased local GTP levels in cell protrusions, decreased RAC1 activity, and hindered cancer cell invasion. The post-translational mechanisms that regulate IMPDH2 function in cancer remain largely unknown. My preliminary data demonstrate that previously unidentified IMPDH2 acetylation regulates its activity and invasion of cancer cells. Furthermore, we identified a potential acetyltransferase that could be responsible for this modification. Therefore, in the current proposal, I will reveal the role of IMPDH2 acetylation in IMPDH2- dependent GTP production, major GTP-dependent cellular processes, and melanoma cell tumorigenicity and metastasis. I will also identify the molecular mechanisms underlying the role of the identified acetyltransferase in IMPDH2-dependent processes in melanoma cells. I will accomplish these aims and my overall research training plan using the multitude of resources within my training environment, with full support from my sponsor.


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 = $50,114 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Research Manpower	000	1	8/11/2026	NEW	$50,114
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Research Manpower	001	1	8/11/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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ATAT1-Driven Acetylation as a Mechanism for IMPDH2 Regulation in Melanoma

Award Number: F31CA317823

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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