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Targeting Ubiquitin Signaling vulnerabilities in KEAP1-Inactivated Lung Cancer

ABSTRACT: Lung cancer cells rely on protein homeostasis regulators, especially within the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. We have investigated how these changes drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer vulnerabilities, including KEAP1.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Lung Cancer

SUBMITTER: Rubina Kazi

LAB HEAD: Prof. Ivan Dikic

PROVIDER: PXD067472 | Pride | 2026-02-04

REPOSITORIES: Pride

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			Action	DRS
	20250228_LU_LC1_MAA_RK_12346_01_F01.raw	Raw
	20250228_LU_LC1_MAA_RK_12346_01_F02.raw	Raw
	20250228_LU_LC1_MAA_RK_12346_01_F03.raw	Raw
	20250228_LU_LC1_MAA_RK_12346_01_F04.raw	Raw
	20250228_LU_LC1_MAA_RK_12346_01_F05.raw	Raw

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Targeting Ubiquitin Signaling vulnerabilities in KEAP1-Inactivated Lung Cancer

Project description:Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these changes drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer vulnerabilities, including KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated NRF2 and upregulated Aldh3a1. This led to elevated NADH/NAD⁺ ratios, triggered reductive stress, and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.

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Targeting Ubiquitin Signaling vulnerabilities in KEAP1-Inactivated Lung Cancer

Project description:Targeting Ubiquitin Signaling vulnerabilities in KEAP1-Inactivated Lung Cancer

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Quantitative proteome dataset profiling of UBC4 and UBC5 deletion strains in Saccharomyces cerevisiae v

Project description:The Ubiquitin-Proteasome System (UPS) regulates many cellular processes in eukaryotic cells. Ubiquitylation by the UPS mainly directs proteins to proteasomal degradation, but it can also have non-degradative functions, such as regulating protein activity or localization. The small protein ubiquitin is conjugated to its substrates via a cascade of E1-E2-E3 enzymes. Dysregulation of the UPS has been implicated in the genesis and progression of many diseases, such as neurodegenerative diseases and cancer; thus, the UPS components are attractive targets for developing pharmaceutical drugs. E2s, or ubiquitin conjugating enzymes, are central players of the UPS. E2s function in tandem with specific ubiquitin ligases (E3s) to transfer ubiquitin to substrates. Here, we present the first proteome stability analysis of two closely related ubiquitin conjugating enzymes, UBC4 and UBC5, in S. cerevisiae. These two E2s are nearly identical, having 92% sequence identity and differing by only 11 amino acid residues. This dataset is of broad interest because higher eukaryotes express ubiquitin conjugating enzymes that are analogous to the yeast UBC4/5.

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Project description:The Ubiquitin Proteasome System (UPS) governs numerous cellular processes by modulating protein stability and activity via the conjugation of the small molecule ubiquitin, either as a single chain or as linkages with distinct functions. Dysregulation of the UPS has been associated with many diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Ubiquitin conjugating enzymes (E2s) are important players of the UPS which work together with ubiquitin ligases (E3s) to promote substrate ubiquitylation. In this study, we conduct a comparative proteome-wide abundance profiling of S. cerevisiae cells during exponential growth phase with and without heat shock treatment. We focus on cells with deletions of the two highly homologous E2s, UBC4 or UBC5, and use isobaric tag-based quantitative mass spectrometry to elucidate variations and similarities in their proteome profiles. Our analysis revealed that Ubc4 has a much stronger effect on the proteome compared to Ubc5, particularly in exponentially growing cells. In contrast, the effect of Ubc5 on the proteome only becomes evident after heat shock, and even then, it remains minor compared to Ubc4. Furthermore, we identified proteins increasing in absence of each enzyme, which may represent their candidate substrates, potentially contributing to a better understanding of their cellular role.

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2022-07-05 | PXD028802 | Pride

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