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Dissecting Nrf2-dependent HIF1a activation mechanism in arsenic-induced cancer stem-like cells

Award Number: R01ES031822
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Dissecting Nrf2-dependent HIF1a activation mechanism in arsenic-induced cancer stem-like cells - Long-term exposure to arsenic, esp. the inorganic trivalent arsenic (iAs), a human carcinogen that occurs naturally in the earth's crust or work place due to industrial settings, has been linked to various types of cancers, esp. lung cancer. It has been known for decades that multiple different mechanisms might be involved in iAs-induced malignant transformation. However, whether and how iAs induces cancer stem-like cells (CSCs) from non-stem cells hadn’t been studied. We had previously shown that consecutive treatment of the human bronchial epithelial cells with 0.125 to 0.25 M (~9 to 18ppb) iAs for six months induced generation of the CSCs. In addition to the higher expression of the stemness circuit genes, including Oct4, Sox2, myc, Klf4, etc., these iAs-induced CSCs also exhibited a unique metabolic pattern featured with an active glycolysis and diminished mitochondrial oxidative phosphorylation (OXPHOS). ChIP-seq analysis of the parental cells and the iAs-induced CSCs revealed a substantial increase in the enrichment of histone H3 lysine4 trimethylation (H3K4me3), an active epigenetic marker for gene transcription, among genes critical for the stemness and glycolysis of the CSCs. To understand how iAs induces these metabolic and epigenetic changes and the generation of the CSCs, we recently also investigated the capability of iAs on the activation of Nrf2 and HIF1 signaling through both biochemical and ChIP-seq approaches. The data indicate that Nrf2 and HIF1 may serve as initiators for the metabolic and epigenetic reprograming, and the acquisition of the CSC features. Accordingly, we hypothesize that iAs-activated Nrf2 is an upstream activator for HIF1 signaling linked to glycolysis, and the subsequent epigenetic reprogramming and generation of the CSCs. To test this hypothesis, the following three specific aims will be pursued: Aim1, dissecting Nrf2 activation pathways with an emphasis on the iAs-induced ubiquitination and degradation of Keap1, the endogenous inhibitor of Nrf2; Aim 2, investigating mechanisms of Nrf2-dependent initiation of HIF1 signaling in the cells in response to iAs; and Aim 3, understanding how iAs-induced Nrf2-HIF1 signaling shifts the metabolism from mitochondrial TCA cycle to glycolysis that linked to reprogramming of the histone methylation profiles and the generation of CSCs. We expect that the data from the completion of this research plan will be the first to reveal the importance of Nrf2 and HIF1 in iAs- induced CSCs, which may be translated into new strategies of cancer therapy by targeting the Nrf2- HIF1 signaling and the CSCs.


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 = $355,512 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	6	10/28/2024	NON-COMPETING CONTINUATION	$355,512
														Subtotal = $355,512

Issue Date FY: 2024 ( Subtotal = $355,512 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	5	10/19/2023	NON-COMPETING CONTINUATION	$355,512
														Subtotal = $355,512

Issue Date FY: 2023 ( Subtotal = $355,512 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	4	11/1/2022	NON-COMPETING CONTINUATION	$355,512
														Subtotal = $355,512

Issue Date FY: 2022 ( Subtotal = $355,512 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	3	10/27/2021	NON-COMPETING CONTINUATION	$355,512
2022	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	001	1	11/6/2021	NEW	-$355
2022	2021	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	002	2	11/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$355
														Subtotal = $355,512

Issue Date FY: 2021 ( Subtotal = $353,383 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	002	2	9/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$294,076
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	1	12/9/2020	NEW	$346,500
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	001	1	9/14/2021	NEW	-$287,193
														Subtotal = $353,383

Grand Total All Awards = $1,775,431

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Dissecting Nrf2-dependent HIF1a activation mechanism in arsenic-induced cancer stem-like cells

Award Number: R01ES031822

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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