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Histone Deacetylation Signaling in Aging and Cancer Pathways

Award Number: R01CA268925
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Histone Deacetylation Signaling in Aging and Cancer Pathways - Our broad research goal is to understand chromatin regulatory mechanisms in nuclear and epigenetic programs and how these mechanisms are deregulated in aging and disease. A fundamental mechanism for regulating chromatin involves the reversible modification of histones by chemical moieties such as acetyl-, methyl-, and phospho-groups. These different histone marks are linked to discrete chromatin states and regulate the accessibility of DNA to transacting factors. In budding yeast, histone deacetylation by the chromatin silencing factor Sir2 prevents genomic instability and aging, and in mammals, de-regulation of histone acetylation is linked to cellular senescence and aging-related pathologies from neurodegeneration to cancer. Here, we focus on SIRT7, a chromatin regulatory, lysine deacetylase enzyme in the Sir2 family of aging-regulatory factors. This project will study new roles of SIRT7-dependent histone deacetylation in chromatin regulatory mechanisms that are deregulated in aging and age-associated cancer biology. Inactivation of SIRT7 in mice leads to genomic instability, shortened lifespan and aging-related phenotypes, and preliminary studies suggest that increased SIRT7 protects against aging pathologies in mice. However, SIRT7 can also sustain oncogenic transcriptional programming in cancer cells. Thus, uncovering distinct pathways of SIRT7 chromatin regulation, may be important to dissect pleiotropic functions of SIRT7 in aging and cancer pathways. Recently, we identified a novel substrate of SIRT7, acetylated lysine K36 of histone H3 (H3K36ac), which is dramatically hyper-acetylated upon SIRT7-inactivation. H3K36ac is implicated in chromatin remodeling and DNA damage responses in yeast, but its regulation and functions in mammalian biology are largely obscure. In preliminary studies we found that the increased H3K36 acetylation in SIRT7- deficient cells is coupled to decreased di-methylation at this residue (H3K36me2), a chromatin modification that has important roles in gene activation, DNA methylation and oncogenic transformation. Moreover, SIRT7 interacts physically with the oncoprotein NSD2, the enzyme that generates the bulk of H3K36me2 in many cell types. Here, we will investigate a new model that SIRT7 clears acetylation at H3K36 from large swaths of chromatin to help prime NSD2-catalyzed methylation at H3K36. In Aim 1, we explore the connection of SIRT7 and NSD2 in aging-related processes using genomic, cellular and mouse systems, and in Aim 2, we test the role of SIRT7-H3K36-NSD2 methylation axis in driving lung carcinoma in vivo, using pre-clinical mouse and human cancer models. By uncovering distinct pathways of SIRT7 chromatin regulation, this project may suggst strategies to selectively enhance functions of SIRT7 that are protective in aging without promoting oncogenic SIRT7 activities. Together, these studies should provide insights into fundamental chromatin mechanisms in aging and cancer biology.


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 = $0 )
2026	2025	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	5	6/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $452,432 )
2025	2025	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	5	7/17/2025	NON-COMPETING CONTINUATION	$452,432
														Subtotal = $452,432

Issue Date FY: 2024 ( Subtotal = $495,710 )
2024	2024	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	001	4	7/2/2024	SUPPLEMENT FOR EXPANSION	$65,899
2024	2024	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	4	6/27/2024	NON-COMPETING CONTINUATION	$429,811
														Subtotal = $495,710

Issue Date FY: 2023 ( Subtotal = $509,282 )
2023	2023	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	001	3	9/18/2023	SUPPLEMENT FOR EXPANSION	$65,899
2023	2023	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	3	6/13/2023	NON-COMPETING CONTINUATION	$443,383
														Subtotal = $509,282

Issue Date FY: 2022 ( Subtotal = $445,595 )
2022	2022	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	2	6/22/2022	NON-COMPETING CONTINUATION	$445,595
														Subtotal = $445,595

Issue Date FY: 2021 ( Subtotal = $471,174 )
2021	2021	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	1	7/9/2021	NEW	$471,174
														Subtotal = $471,174

Grand Total All Awards = $2,374,193

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Histone Deacetylation Signaling in Aging and Cancer Pathways

Award Number: R01CA268925

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/09/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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