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Role of O-GlcNAc-ylation on tumor progression

Award Number: R01CA262160
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Role of O-GlcNAc-ylation on tumor progression - Abstract O-linked ß-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to the side chain hydroxyl of a serine or threonine residue on proteins. O-GlcNAcylation controls key signaling and biological processes such as signal transduction, transcription, cell cycle progression, and metabolism. Perturbations in O-GlcNAc homeostasis have been linked with diabetes, cancer, and neurodegenerative diseases. Increased glucose levels channel flux through the Hexoseamine Biosynthetic Pathway (HBP), culminating in increased O-GlcNAc levels. The activity of HBP and consequently cellular O-GlcNAc-ylation are elevated in several cancer types, including breast cancer. We recently reported that inhibiting HBP activity significantly decreased the invasive phenotype of breast tumor cells. We surmised that abundance of glucose, a readily-metabolizable carbohydrate, will drive flux through HBP, resulting in enrichment of a portfolio of proteins that are modified by O-GlcNAc-ylation. Using unbiased proteomics analysis, we identified that elevated glucose culture conditions enrich for O-GlcNAc- modified GLI proteins, transcription factors of the Hedgehog (Hh) pathway. Importantly, we identified that in elevated glucose conditions, O-GlcNAc-modification of GLI exacerbates Hh/GLI activity; and inhibiting HBP mitigated this effect. We hypothesize that HBP-directed O-GlcNAc-ylation fundamentally programs invasive and chemoresistant attributes in tumor cells through activating Hh/GLI signaling. In Aim 1 we will determine the molecular underpinnings of HBP-directed O-GlcNAc-ylation of GLI. We will determine the causes and consequences of GLI O-GlcNAc-ylation. We will first identify engagement of the HBP in O-GlcNAc-modification of GLI proteins. Next, we will undertake investigations to identify establish the mechanistic basis of how HBP signaling engages O-GlcNAc-modified GLI to program invasive and chemoresistant attributes in tumor cells. In Aim 2 we will evaluate the impact of an elevated O-GlcNAc landscape on molecular and cellular attributes of the mammary tumor and the associated immune microclimate using two distinct and complementary syngeneic mouse models of mammary cancer. To enrich the relevance, we will also evaluate human TNBC and PDX model systems. We will test if inhibiting GLI activity, in the context of elevated O-GlcNAc, uncouples the influence of O- GlcNAc-ylation on invasive and chemoresistant attributes of mammary tumor cells. Relevance: Our proposed studies are structured to systematically investigate how O-GlcNAc-driven metabolic reprogramming in cancer cells connects at the molecular level to aberrantly activate Hh/GLI signaling. The cumulative outcomes will create mechanistic understanding of how O-GlcNAc-ylation programs tumor invasion, progression and response to anti-neoplastics.


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: 2025 ( Subtotal = $378,994 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	4	3/3/2025	NON-COMPETING CONTINUATION	$341,096
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$37,898
														Subtotal = $378,994

Issue Date FY: 2024 ( Subtotal = $154,171 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$16,985
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	3	3/21/2024	NON-COMPETING CONTINUATION	$137,186
														Subtotal = $154,171

Issue Date FY: 2023 ( Subtotal = $332,900 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$332,900
														Subtotal = $332,900

Issue Date FY: 2022 ( Subtotal = $339,694 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	1	3/10/2022	NEW	$339,694
														Subtotal = $339,694

Grand Total All Awards = $1,205,759

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Role of O-GlcNAc-ylation on tumor progression

Award Number: R01CA262160

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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