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Molecular and Epigenetic Control of Wnt/b-catenin-mediated oncogenesis by KDM4B

Award Number: R01CA236878
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Molecular and Epigenetic Control of Wnt/b-catenin-mediated oncogenesis by KDM4B - Project Summary/Abstract Abnormal Wnt/β-catenin signaling is associated with various types of human cancers, most notably colorectal cancers (CRCs) due to APC and CTNNB1 (β-catenin) mutations. CRCs are the third most common cancer worldwide and the fourth most common cause of death. Wnt/β-catenin signaling exhibits its oncogenic activities by inducing the expression of Wnt target genes such as CCND1 (Cyclin D1) and MYC (c-Myc) through β-catenin/T cell factor (Tcf)-mediated transcription. Although APC and CTNNB1 mutations play a critical role in human CRC initiation and development, emerging evidence suggests that epigenetic modifications act synergistically in human CRC initiation and development. A small subset of cancer stem cells (CSCs) or cancer initiating cells with the ability to self-renew and maintain the tumor has been isolated from human CRCs. We and others have found that β-catenin/Tcf-mediated transcription is hyperactivated in human colorectal CSCs compared to non-CSC tumor cells. In this application, we identified that lysine-specific demethylase 4B (KDM4B) that erases H3K9me3 marks was highly expressed in human CRCs. The knockdown or pharmacological inhibition of KDM4B in human CRC cells significantly inhibited the expression of Wnt target genes. To explore the functional roles of KDM4B in vivo, we generated Kdm4bflox/flox (Kdm4bf/f) mice that carry conditional Kdm4b alleles. Although the deletion of Kdm4b in mice causes intestinal abnormalities and reduced crypt stem cells, unlike the deletion of β-catenin, we found that mice can tolerate KDM4B deficiency, indicating that targeting KDM4B might provide a safe therapeutic window for the treatment of human CRCs. Consistently, we found that the intestinal deletion of Kdm4b completely inhibited intestinal tumorigenesis in ApcMin/+ mice which develop multiple adenomas in the small intestine due to increased β-catenin/Tcf-mediated transcription. Additionally, we found that KDM4B interacts with the intestinal stem cell transcription factor ASCL2 which serve as a positive feedback to enhance β-catenin/Tcf-mediated transcription. Based on these exciting discoveries, we hypothesize that KDM4B might epigenetically control Wnt/β-catenin-mediated oncogenesis and is required for the tumorigenic potentials of human colorectal CSCs. Using molecular, cellular, genetic and epigenetic approaches, we will determine: 1) Whether the knockout or pharmacological inhibition of KDM4B inhibits CRC tumorigenesis in vivo; 2) Whether KDM4B epigenetically controls tumorigenic potentials and self-renewal of CSCs in human CRCs; 3) How KDM4B epigenetically controls Wnt/β-catenin-mediated transcription and tumorigenesis by erasing H3K9me3. Since histone demethylases are enzymes which can be readily targeted by small molecules inhibitors, novel findings from our studies may lead to develop novel strategies for the treatment of human CRCs and other cancers.


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 = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	6/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $407,110 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	5	4/18/2024	NON-COMPETING CONTINUATION	$21,427
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	12/22/2023	NON-COMPETING CONTINUATION	$385,683
														Subtotal = $407,110

Issue Date FY: 2023 ( Subtotal = $419,965 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	12/15/2022	NON-COMPETING CONTINUATION	$385,683
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	4	3/15/2023	NON-COMPETING CONTINUATION	$34,282
														Subtotal = $419,965

Issue Date FY: 2022 ( Subtotal = $419,961 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$34,278
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	12/23/2021	NON-COMPETING CONTINUATION	$385,683
														Subtotal = $419,961

Issue Date FY: 2021 ( Subtotal = $428,535 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	1/22/2021	NON-COMPETING CONTINUATION	$428,535
														Subtotal = $428,535

Issue Date FY: 2020 ( Subtotal = $428,535 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	1/17/2020	NEW	$428,535
														Subtotal = $428,535

Grand Total All Awards = $2,104,106

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Molecular and Epigenetic Control of Wnt/b-catenin-mediated oncogenesis by KDM4B

Award Number: R01CA236878

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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