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Epigenetic modulation of the TAZ-CAMTA1 transcriptional program by the Ada2a-containing histone acetyltransferase complex

Award Number: R01CA237031
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract TAZ/YAP are transcriptional effectors and proto-oncoproteins of the Hippo pathway, a signal transduction pathway regulating tumor growth and metastasis in multiple cancers including sarcomas. While much has been uncovered with regards to the upstream regulation of TAZ and YAP, little is known about epigenetic regulation of their transcriptional programs, representing a significant gap in knowledge. To address this gap, we utilized the TAZ-CAMTA1 (TC) and YAP-TFE3 (YT) fusion proteins. TC and YT are driving oncoproteins in epithelioid hemangioendothelioma (EHE), a sarcoma arising in adolescents (responsive to PA-16-251, Gene Fusions in Pediatric Sarcomas). TC and YT, hyperactivated forms of TAZ and YAP, are relevant because gene fusions are the most common type of genetic alterations of TAZ/YAP in cancer. Our objective in this proposal is to determine if TC and YT further stimulate TAZ/YAP transcription by altering the epigenome. Our central hypothesis is that TC and YT recruit YEATS2 and ZZZ3, part of the Ada2a-containing (ATAC) histone acetyltransferase complex, which potentiate the TAZ/YAP oncogenic transcriptional programs. This hypothesis is supported by two serial unbiased approaches: BioID mass spectrometry followed by an shRNA screen that identified YEATS2 and ZZZ3 as the proteins most critical for TC driven anchorage independent growth. We plan to test our central hypothesis with the following specific aims utilizing TC, the predominant fusion protein in EHE (85% of EHE): Aim 1) Determine how YEATS2 and ZZZ3 alter the TAZ-CAMTA1 transcriptional program. We will perform ChIP-seq and determine if TC co-localizes with YEATS2 and ZZZ3 on the genome. RNA-seq will be performed in TC expressing cell lines with and without expression of YEATS2 or ZZZ3 to identify their effects on the TC transcriptome. Aim 2) Identify domains of TAZ-CAMTA1, YEATS2, and ZZZ3 required for cellular transformation. The interaction of YEATS2 and ZZZ3 with TC will be dissected by co-immunoprecipitation utilizing deletion mutants. The mutants will be further studied in anchorage independent growth assays we have developed. Aim 3) Determine the contributions of the YEATS2 and ZZZ3 interactions with TAZ-CAMTA1 in vivo. We will use both genetic and pharmacological approaches to inhibit YEATS2/ZZZ3/ATAC function in novel TC transgenic and xenograft sarcoma mouse models and evaluate their effect on tumorigenesis and metastasis. The proposal is innovative because it utilizes TC and YT as well as two serial unbiased approaches to identify YEATS2/ZZZ3/ATAC as novel epigenetic regulators of the TAZ/YAP transcriptome, expanding the focus of the field and addressing a significant gap in knowledge. The project is significant because it identifies YEATS2 and ZZZ3 as novel oncoproteins and drivers in sarcoma and provides a rationale for inhibiting histone modifying complexes as a novel way of targeting the Hippo pathway, which currently lacks a therapeutic target.


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: 2024 ( Subtotal = $330,792 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$17,411
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	5	11/15/2023	NON-COMPETING CONTINUATION	$313,381
														Subtotal = $330,792

Issue Date FY: 2023 ( Subtotal = $341,237 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	002	4	3/15/2023	NON-COMPETING CONTINUATION	$27,856
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	4	12/15/2022	NON-COMPETING CONTINUATION	$313,381
2023	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	3	12/14/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $341,237

Issue Date FY: 2022 ( Subtotal = $414,270 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	3	11/16/2021	NON-COMPETING CONTINUATION	$313,382
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	004	3	8/22/2022	NON-COMPETING CONTINUATION	$6,964
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	3	11/19/2021	SUPPLEMENT FOR EXPANSION	$59,463
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	003	3	5/20/2022	SUPPLEMENT FOR EXPANSION	$6,606
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	002	3	4/27/2022	NON-COMPETING CONTINUATION	$27,855
														Subtotal = $414,270

Issue Date FY: 2021 ( Subtotal = $414,270 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$393,557
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	2	1/22/2021	NON-COMPETING CONTINUATION	$20,713
														Subtotal = $414,270

Issue Date FY: 2020 ( Subtotal = $371,153 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	1	12/3/2019	NEW	$348,201
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	1	8/17/2020	SUPPLEMENT FOR EXPANSION	$22,952
														Subtotal = $371,153

Grand Total All Awards = $1,871,722

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Epigenetic modulation of the TAZ-CAMTA1 transcriptional program by the Ada2a-containing histone acetyltransferase complex

Award Number: R01CA237031

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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