A Novel Gene Signature Associated With “E2F Target” Pathway for Predicting the Prognosis of Prostate Cancer

Xia, Haoran; Wang, Miaomiao; Su, Xiaonan; Lv, Zhengtong; Yan, Qiuxia; Guo, Xiaoxiao; Liu, Ming

doi:10.3389/fmolb.2022.838654

Cited by 4 publications

(4 citation statements)

References 47 publications

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“…NEPC has been defined as a disease that is highly transcriptionally active regulating proteins involved in DNA replication (for example DNA polymerase, thymidine kinase, dihydrofolate reductase and cdc6), and chromosomal regulation ( 60 ), whereas prostate cancer AdCa that expresses AR and without neuroendocrine features is highly metabolically ( 61 ) regulated. Furthermore, it has been shown that mRNA from transcription factors have increased average decay rates compared with other mRNA transcripts and are enriched for “fast-decaying” mRNA transcripts with half-lives <2 hours ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts

Sychev,

Day,

Bergom

et al. 2024

Molecular Cancer Research

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Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. In this work, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. We compared 15 NE versus 33 AdCa samples, that included six different PDX tumors for each group in biological replicates and identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of concordance from PDX tumor matched protein and mRNA revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa. Implications: Overall, our study highlights the importance of protein-based identification when compared to RNA and provides a rich resource of new and feasible targets for clinical assay development and in understanding the underlying biology of these tumors.

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Section: Discussionmentioning

confidence: 99%

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts

Sychev,

Day,

Bergom

et al. 2024

Molecular Cancer Research

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“…Several E2F target genes are tightly connected, which may help predict tumor prognosis. An E2F target gene signature, formed by MDX3, PLK1, EPHA10, and KIF4A, exhibited a stronger predictive power than existing signatures in prostate cancer ( Xia et al, 2022 ). Hu et al (2022) established an E2F target gene signature composed of five genes (HN1, KIF4A, CDCA3, CDCA8, and SSRP1) and found it is significantly related to the prognosis of hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…E2Fs detach from the E2F-RB1 complex and promote cell cycle-dependent gene transcription when RB1 is altered or phosphorylated ( van den Heuvel and Dyson, 2008 ; Zheng et al, 2023 ). Upregulation of E2F target genes is correlated with poor outcomes of neuroblastoma, breast cancer, colorectal cancer, ovarian cancer, and prostate cancer ( Molenaar et al, 2012 ; Dahl et al, 2019 ; Oshi et al, 2021 ; Xia et al, 2022 ; Xu et al, 2022 ). Moreover, the E2F score serves as a predictive biomarker of response to neoadjuvant chemotherapy in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients ( Oshi et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Three E2F target-related genes signature for predicting prognosis, immune features, and drug sensitivity in hepatocellular carcinoma

Zhang,

Chang,

Wang

et al. 2023

Front. Mol. Biosci.

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Background: Hepatocellular carcinoma (HCC) is extremely malignant and difficult to treat. The adenoviral early region 2 binding factors (E2Fs) target pathway is thought to have a major role in tumor growth. This study aimed to identify a predictive E2F target signature and facilitate individualized treatment for HCC patients.Methods: We constructed an E2F target-related gene profile using univariate COX and LASSO regression models and proved its predictive efficacy in external cohorts. Furthermore, we characterized the role of the E2F target pathway in pathway enrichment, immune cell infiltration, and drug sensitivity of HCC.Results: Lasso Cox regression created an E2F target-related gene signature of GHR, TRIP13, and CDCA8. HCC patients with high risk were correlated with shorter survival time, immune evasion, tumor stem cell characteristics and high sensitivity to Tipifarnib and Camptothecin drugs.Conclusion: Hepatocellular carcinoma prognosis was predicted by an E2F target signature. This finding establishes the theoretical usefulness of the E2F target route in customized identification and treatment for future research.

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“…E2F1 and E2F2 are upregulated in several cancer types, including prostate cancer (PCa) [7,8], in which overexpression of these E2Fs correlates with poor clinical outcome [9,10]. In this regard, it has been suggested that cancer cells rely on E2F function to tolerate the exceptionally high levels of basal or drug-induced DNA replication stress that cancer cells endure [11,12].…”

Section: Introductionmentioning

confidence: 99%

Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity

Hamidi

Eriz

Mitxelena

et al. 2022

Cancers

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E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F in PCa, we analyzed the contribution of E2F target genes to the control of genome integrity, and the impact of modulating E2F activity on PCa progression. We show that silencing or inhibiting E2F1/E2F2 induces DNA damage during S phase and potentiates 5-FU-induced replication stress and cellular toxicity. Inhibition of E2F downregulates the expression of E2F targets involved in nucleotide biosynthesis (TK1, DCK, TYMS), whose expression is upregulated by 5-FU. However, their enzymatic products failed to rescue DNA damage of E2F1/E2F2 knockdown cells, suggesting additional mechanisms for E2F function. Interestingly, targeting E2F1/E2F2 in PCa cells reduced WEE1 expression and resulted in premature CDK1 activation during S phase. Inhibition of CDK1/CDK2 prevented DNA damage induced by E2F loss, suggesting that E2F1/E2F2 safeguard genome integrity by restraining CDK1/CDK2 activity. Importantly, combined inhibition of E2F and ATR boosted replication stress and dramatically reduced tumorigenic capacity of PCa cells in xenografts. Collectively, inhibition of E2F in combination with drugs targeting nucleotide biosynthesis or DNA repair is a promising strategy to provoke catastrophic levels of replication stress that could be applied to PCa treatment.

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A Novel Gene Signature Associated With “E2F Target” Pathway for Predicting the Prognosis of Prostate Cancer

Cited by 4 publications

References 47 publications

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts

Three E2F target-related genes signature for predicting prognosis, immune features, and drug sensitivity in hepatocellular carcinoma

Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity

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