Deregulated E2F Activity as a Cancer-Cell Specific Therapeutic Tool

Nakajima, Rinka; Zhao, Lin; Zhou, Yaxuan; Shirasawa, Mashiro; Uchida, Ayato; Murakawa, Hikaru; Fikriyanti, Mariana; Iwanaga, Ritsuko; Bradford, Andrew P.; Araki, Keigo; Warita, Tomoko; Ohtani, Kiyoshi

doi:10.3390/genes14020393

Cited by 9 publications

(4 citation statements)

References 159 publications

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“…These genes are found in multiple hallmark pathways (allograft rejection, MYC targets, E2F targets, etc.) that have been associated with cancer initiation and progression [ 37 – 39 ], especially in hematologic malignancies [ 40 ]. It is important to mention that we were unable to identify a gene set signature for resistant cell lines using ascending GSEA when the same methodology was applied (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Beauchamp,

Gamma,

Cromwell

et al. 2024

J Transl Med

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Background In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. Methods and results Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. Conclusions Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Beauchamp,

Gamma,

Cromwell

et al. 2024

J Transl Med

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“…The E2F family consists of eight transcription factors that encode 10 proteins, which play critical roles in various biological processes such as genomic integrity, cell cycle development, differentiation, metabolism, and apoptosis. [34,35] These transcription factors are highly abundant in cancer and have been implicated as inducers of several human carcinomas, including breast, colon, oral, and PCa. [36] Among the E2F family, E2F1 is particularly essential for the development of PCa.…”

Section: Discussionmentioning

confidence: 99%

Oncogene goosecoid is transcriptionally regulated by E2F1 and correlates with disease progression in prostate cancer

Ge,

Ma,

Zhou

et al. 2023

Chinese Medical Journal

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Background: Although some well-established oncogenes are involved in cancer initiation and progression such as prostate cancer (PCa), the long tail of cancer genes remains to be defined. Goosecoid (GSC) has been implicated in cancer development. However, the comprehensive biological role of GSC in pan-cancer, specifically in PCa, remains unexplored. The aim of this study was to investigate the role of GSC in PCa development. Methods: We performed a systematic bioinformatics exploration of GSC using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, German Cancer Research Center, and our in-house cohorts. First, we evaluated the expression of GSC and its association with patient prognosis, and identified GSC-relevant genetic alterations in cancers. Further, we focused on the clinical characterization and prognostic analysis of GSC in PCa. To understand the transcriptional regulation of GSC by E2F transcription factor 1 (E2F1), we performed chromatin immunoprecipitation quantitative polymerase chain reaction (qPCR). Functional experiments were conducted to validate the effect of GSC on the tumor cellular phenotype and sensitivity to trametinib. Results: GSC expression was elevated in various tumors and significantly correlated with patient prognosis. The alterations of GSC contribute to the progression of various tumors especially in PCa. Patients with PCa and high GSC expression exhibited worse progression-free survival and biochemical recurrence outcomes. Further, GSC upregulation in patients with PCa was mostly accompanied with higher Gleason score, advanced tumor stage, lymph node metastasis, and elevated prostate-specific antigen (PSA) levels. Mechanistically, the transcription factor, E2F1, stimulates GSC by binding to its promoter region. Detailed experiments further demonstrated that GSC acted as an oncogene and influenced the response of PCa cells to trametinib treatment. Conclusions: GSC was highly overexpressed and strongly correlated with patient prognosis in PCa. We found that GSC, regulated by E2F1, acted as an oncogene and impeded the therapeutic efficacy of trametinib in PCa.

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“…However, both constructs showed similar cytotoxicity in cancer cell lines [193]. These observations suggest that utilizing deregulated E2F activity by the ARF promoter is superior to that by the E2F1 promoter to drive gene expression specifically in cancer cells [194]. Upon dysfunction of the RB pathway, deregulated E2F1 activates the Arf gene to protect cells from tumorigenesis.…”

Section: E2f1 Targets Involved In P53-independent Pathways For the In...mentioning

confidence: 92%

Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression

Zhou,

Nakajima,

Shirasawa

et al. 2023

Biology

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The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.

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Deregulated E2F Activity as a Cancer-Cell Specific Therapeutic Tool

Cited by 9 publications

References 159 publications

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Oncogene goosecoid is transcriptionally regulated by E2F1 and correlates with disease progression in prostate cancer

Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression

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