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Usp16-Mediated Histone H2A Deubiquitination Regulates Breast Cancer Cell Invasion

Award Number: SC3GM132056
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Usp16-Mediated Histone H2A Deubiquitination Regulates Breast Cancer Cell Invasion - PROJECT SUMMARY/ABSTRACT Many important cellular events are regulated by antagonistic mechanisms, and understanding how factors involved in the regulation of tumorigenesis execute their antagonistic functions is particularly important. Histone H2A mono-ubiquitination at K119 mediated by polycomb repressive complex 1 (PRC1) is an important epigenetic mark associated with epithelial-mesenchymal transition (EMT) and cell invasion during early metastasis. However, less is known about the function of histone H2A deubiquitination during these processes. Our long-term research goal is to elucidate the molecular mechanism underlying the regulation of histone H2A ubiquitination and deubiquitination, and determine the role of this histone modification in the regulation of cell cycle and tumorigenesis. To this end, the goal of the proposed research is to study the function of histone H2A deubiquitination mediated by ubiquitin specific peptidase 16 (USP16) in the regulation of EMT and invasion of breast cancer cells. Our preliminary data has shown that BMI1, a member of PRC1, promotes EMT and invasion of breast cancer cells. Since USP16 specifically deubiquitinates H2A at K119, the central hypothesis of this application is that the USP16 antagonizes the function of BMI1 and inhibits the EMT and invasion of breast cancer cells. Furthermore, we have previously identified USP16 as a novel substrate of polo-like kinase 1 (PLK1). Therefore, the role of PLK1 in USP16-mediated regulation of EMT and cell invasion will also be determined. The rationale for this hypothesis rests on the following: once the role of USP16-mediated H2A deubiquitination in the regulation of EMT and invasion of cancer cells is established, a novel tumorigenesis regulatory mechanism that involves both the ubiquitination and deubiquitination of H2A can be defined. The central hypothesis will be tested through the activities including: (1) Determine whether USP16-mediated deubiquitination of histone H2A inhibits EMT and invasion of breast cancer cells. Following overexpression and knockdown of USP16, the changes in the expression of EMT markers and invasiveness of breast cancer cells will be analyzed. (2) Determine the role of PLK1 in USP16-mediated regulation of EMT and invasion of breast cancer cells. As the phosphorylation sites on USP16 have been identified, we will utilize both non- phosphorylatable and phosphomimic USP16 constructs to carefully evaluate the function of USP16 phosphorylation by PLK1 in regulating EMT and cell invasion. The expected outcomes of this study include the identification of ubiquitination and deubiquitination of histone H2A as an important mechanism for the regulation of metastasis in breast cancer, and the revealing of a cell cycle regulation-independent function of PLK1 in tumorigenesis. Knowledge of these mechanisms may contribute to the development of novel approaches in the prevention and treatment of metastatic breast cancer. !


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 = $0 )
2024	2022	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	8/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $110,250 )
2022	2022	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	6/20/2022	NON-COMPETING CONTINUATION	$11,025
2022	2022	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	3/15/2022	NON-COMPETING CONTINUATION	$99,225
														Subtotal = $110,250

Issue Date FY: 2021 ( Subtotal = $110,250 )
2021	2021	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	3/24/2021	NON-COMPETING CONTINUATION	$110,250
														Subtotal = $110,250

Issue Date FY: 2020 ( Subtotal = $103,200 )
2020	2020	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/26/2020	NON-COMPETING CONTINUATION	$103,200
														Subtotal = $103,200

Issue Date FY: 2019 ( Subtotal = $96,526 )
2019	2019	CAL POLY POMONA FOUNDATION INC	3801 W TEMPLE AVE	POMONA	CA	91768	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/6/2019	NEW	$96,526
														Subtotal = $96,526

Grand Total All Awards = $420,226

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Usp16-Mediated Histone H2A Deubiquitination Regulates Breast Cancer Cell Invasion

Award Number: SC3GM132056

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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