Tuesday, August 19, 2025 8/19/2025

Dissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression

Award Number: R01CA273231
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Dissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression - Project Summary Dissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide and associated with high mutation burdens. During the last decade, biomarker-driven targeted therapies have achieved clear clinical benefits in patients with several oncogenic driver mutations such as EGFR, BRAF and ALK. However, the treatments for tumors with the most prevalent KRAS mutations remain challenging despite of recent breakthrough in targeting KRAS-G12C mutation. In KRAS mutant NSCLC, the constitutively activated downstream signaling ultimately leads to transcription reprogramming to sustain tumor growth and progression. This process is orchestrated by a cohort of crucial transcription factors, whose temporal and spatial expression is associated with distinct epigenetic changes. Thus, dissecting epigenetic mechanisms in this process could open new avenues for targeting strategies. SETDB1 is a principal methyltransferase catalyzing histone H3K9 methylation, a major repressive epigenetic modification. The focal amplification and upregulation of SETDB1 have been observed in a wide range of cancers including NSCLC, suggesting it has pro-oncogenic function. However, the mechanisms of action of SETDB1 in NSCLC remain elusive. In preliminary study, we uncovered that SETDB1 upregulation in lung adenocarcinoma (ADC) correlates with poorer prognosis and significantly co-occurs with KRAS gene alternations. In NSCLC cells harboring oncogenic RAS, SETDB1 loss attenuates migration and invasion, invadopodia formation and ECM degradation. These phenotypic changes correlate with reactivation of transcription factors FOXA2 and CDX2 which function as key regulatory nodes to impede metastatic progression of KRAS mutant lung ADC. More importantly, Setdb1 loss in tumor cells derived from metastatic KrasG12D;p53fl/fl lung ADC abolished their spontaneous ability to metastasize from the subcutaneous tumor to the lungs. These findings argue for a novel concept that SETDB1-mediated epigenetic mechanisms are critical for oncogenic KRAS-induced transcription reprogramming during lung ADC progression. Moreover, we have demonstrated that SETDB1 is monoubiquitinated at lysine-867 by the UBE2E family of E2 enzymes independent of E3s and this monoubiquitination is essential for SETDB1-mediated H3K9 methylation and ERV silencing. Accordingly, one objective of this proposal is to delineate SETDB1's pro-metastatic activity in KRAS mutant lung ADC using various genetically engineered mouse models and xenograft models. Another objective is to dissect the mechanisms of lysine-867 monoubiquitination in SETDB1's pro-metastatic activity in vivo and in vitro. Our central hypothesis is that SETDB1 plays important roles in KRAS mutant lung ADC progression through epigenetic mechanisms that require its monoubiquitination dependent enzymatic activity. This project is significant because it will characterize SETDB1 as an actionable drug target in KRAS mutant lung cancer and identify novel molecular interfaces for targeting. Our long-term goal is to develop better and more effective therapeutic strategies by delineating epigenetic mechanisms in lung 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: 2025 ( Subtotal = $402,086 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	4	7/22/2025	NON-COMPETING CONTINUATION	$402,086
														Subtotal = $402,086

Issue Date FY: 2024 ( Subtotal = $381,884 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	3	7/19/2024	NON-COMPETING CONTINUATION	$381,884
														Subtotal = $381,884

Issue Date FY: 2023 ( Subtotal = $394,014 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	2	7/20/2023	NON-COMPETING CONTINUATION	$394,014
														Subtotal = $394,014

Issue Date FY: 2022 ( Subtotal = $401,691 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	1	7/30/2022	NEW	$401,691
														Subtotal = $401,691

Grand Total All Awards = $1,579,675

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Dissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression

Award Number: R01CA273231

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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