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Hydroxylation regulation of c-Myc

Award Number: R01CA186241
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Hydroxylation regulation of c-Myc - Project Summary Aberrant overexpression and activation of c-MYC contributes to most human cancers by regulating virtually all of the cancer hallmarks. Therefore, c-MYC levels and activity must be tightly regulated during normal cell homeostasis, including through posttranslational regulation. c-MYC normally undergoes rapid turnover via ubiquitin-dependent proteolysis mediated by the threonine 58 phosphorylation-dependent ubiquitin ligase complex SCFFbw7 and over a dozen other ubiquitin E3s. Conversely, c-MYC ubiquitination can be reversed by several deubiquitinating enzymes (DUBs), including USP28 and USP36. In addition, c-MYC can be modified by SUMOylation and its deSUMOylation by SENP1 stabilizes c-MYC. However, whether c-MYC is regulated by proline hydroxylation is not known. We have recently discovered that the proline hydroxylase PHD3 is a novel c-MYC regulator. PHD3 binds to c-MYC in cells and in vitro. Knockdown of PHD3 markedly increases the levels and activity of c-MYC, leading to a marked increase in aerobic glycolysis and cancer cell proliferation. PHD3 promotes c-MYC hydroxylation and interaction with pVHL dependent on PHD3’s proline hydroxylase activity. Intriguingly, knockdown of PHD3 also increases c-MYC levels under hypoxia, suggesting that PHD3, which is strongly induced by hypoxia, still regulates c-MYC levels and activity during low oxygen tension via a compensation mechanism. These preliminary data lead to the unique hypothesis that PHD3 is a novel negative regulator of c-MYC by mediating c-MYC proline hydroxylation and pVHL-mediated ubiquitination. To gain further insight into the role of PHD3 in regulating c-MYC protein stability, activity and oncogenicity, we will investigate the molecular and biochemical mechanisms of the regulation of c-MYC by PHD3 in Aim 1, including identifying and confirming c-MYC proline hydroxylation sites, how proline hydroxylation promotes pVHL-mediated c-MYC degradation and whether PHD3 regulates c-MYC-HIF crosstalk under hypoxia. Aim 2 will analyze PHD3 regulation of c-MYC DNA binding and turnover at target gene promoters, whether this regulation crosstalks with the HIF transcriptional program in response to hypoxia. As we observed that PHD3 is frequently down-regulated in human breast cancers, in Aim 3 we will investigate whether PHD3 suppresses c- MYC-driven transformation and whether genetic deletion of PHD3 potentiates c-MYC-driven tumorigenesis and whether re-activation of PHD3 suppresses c-MYC-driven mammary tumorigenesis in vivo. Achieving these goals will provide critical insight into how c-MYC is properly regulated by PHD3-mediated proline hydroxylation, how PHD3 deregulation of c-MYC contributes to hypoxia adaptation and tumorigenesis, and whether PHD3 is a promising therapeutic target in human breast 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: 2026 ( Subtotal = $453,182 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	11	3/27/2026	COMPETING CONTINUATION	$453,182
2026	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	10	3/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $453,182

Issue Date FY: 2024 ( Subtotal = $360,701 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	10	5/7/2024	NON-COMPETING CONTINUATION	$360,701
														Subtotal = $360,701

Issue Date FY: 2023 ( Subtotal = $372,091 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	9	5/17/2023	NON-COMPETING CONTINUATION	$372,091
														Subtotal = $372,091

Issue Date FY: 2022 ( Subtotal = $386,742 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	8	4/22/2022	NON-COMPETING CONTINUATION	$386,742
														Subtotal = $386,742

Issue Date FY: 2021 ( Subtotal = $394,637 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	002	7	5/27/2021	NON-COMPETING CONTINUATION	$394,637
2021	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	6	11/16/2020	COMPETING CONTINUATION	$44,634
2021	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	5	11/16/2020	NON-COMPETING CONTINUATION	-$44,634
														Subtotal = $394,637

Issue Date FY: 2020 ( Subtotal = $379,685 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	6	5/29/2020	COMPETING CONTINUATION	$379,685
2020	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	5	5/22/2020	NON-COMPETING CONTINUATION	$0
2020	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	002	5	7/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,685

Issue Date FY: 2019 ( Subtotal = $365,173 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	5	3/8/2019	NON-COMPETING CONTINUATION	$365,173
														Subtotal = $365,173

Issue Date FY: 2018 ( Subtotal = $376,467 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	4	3/9/2018	NON-COMPETING CONTINUATION	$338,821
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	4	5/23/2018	NON-COMPETING CONTINUATION	$37,646
														Subtotal = $376,467

Issue Date FY: 2017 ( Subtotal = $376,467 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	3	6/7/2017	NON-COMPETING CONTINUATION	$37,646
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	3	3/8/2017	NON-COMPETING CONTINUATION	$338,821
														Subtotal = $376,467

Issue Date FY: 2016 ( Subtotal = $383,331 )
2016	2016	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	2	3/17/2016	NON-COMPETING CONTINUATION	$383,331
														Subtotal = $383,331

Issue Date FY: 2015 ( Subtotal = $395,640 )
2015	2015	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	1	2/11/2015	NEW	$395,640
														Subtotal = $395,640

Grand Total All Awards = $4,244,116

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Hydroxylation regulation of c-Myc

Award Number: R01CA186241

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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