Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma

Dong, Jiaqiang; Li, Jiong; Li, Yang; Ma, Zhikun; Yu, Yongxin; Wang, Cun‐Yu

doi:10.1038/s41467-021-24137-1

Cited by 80 publications

(60 citation statements)

References 37 publications

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“…While the role of PogZ in cancer is poorly understood, this protein was reported to interact with HRP2 in cancer cells to facilitate DNA repair [29,63]. Med-1, a mediator of RNAPII transcription and interactor of the bromodomain protein 4 (BRD4), an SE assembly protein, was recently implicated in leukemia chemoresistance via interaction with LEDGF/p75 [15] and in enhancing the stemness and metastasis of squamous cell carcinoma via SE formation [64].…”

Section: Discussionmentioning

confidence: 99%

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells

Ortiz-Hernández

Sanchez-Hernández

Ochoa

et al. 2021

Cells

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Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells

Ortiz-Hernández

Sanchez-Hernández

Ochoa

et al. 2021

Cells

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“…Then, the staining declines toward the tumor center [36,81]. Moreover, higher FOSL1 levels may indicate the presence of metastases since specimens taken from patients with metastases in the liver [36] and the lymph nodes [82] exhibit more intense staining for FOSL1 than the tumor samples taken from the patients that do not have metastases.…”

Section: Role Of Fosl1 In Tumorigenesis 41 Fosl1 Expression Pattern I...mentioning

confidence: 99%

Role of the Transcription Factor FOSL1 in Organ Development and Tumorigenesis

Соболев

Хашукоева

Evina

et al. 2022

IJMS

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The transcription factor FOSL1 plays an important role in cell differentiation and tumorigenesis. Primarily, FOSL1 is crucial for the differentiation of several cell lineages, namely adipocytes, chondrocytes, and osteoblasts. In solid tumors, FOSL1 controls the progression of tumor cells through the epithelial–mesenchymal transformation. In this review, we summarize the available data on FOSL1 expression, stabilization, and degradation in the cell. We discuss how FOSL1 is integrated into the intracellular signaling mechanisms and provide a comprehensive analysis of FOSL1 influence on gene expression. We also analyze the pathological changes caused by altered Fosl1 expression in genetically modified mice. In addition, we dedicated a separate section of the review to the role of FOSL1 in human cancer. Primarily, we focus on the FOSL1 expression pattern in solid tumors, FOSL1 importance as a prognostic factor, and FOSL1 perspectives as a molecular target for anticancer therapy.

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“…Finally, investigations have shown that SEs are crucial for the survival of HNSCC cancer stem cells. Perturbation of SE-mediated transcription led to the elimination of these cells [46]. CDK7 overexpression has been observed in many cancer entities and generally indicates a worse prognosis and is associated with aggressive clinicopathological features.…”

Section: Discussionmentioning

confidence: 99%

CDK7 Predicts Worse Outcome in Head and Neck Squamous-Cell Cancer

Jagomast

Idel

Klapper

et al. 2022

Cancers

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HNSCC is the sixth most common cancer worldwide and the prognosis is still poor. Here, we investigated the prognostic implications of CDK7 and pMED1. Both proteins affect transcription, and their expression is altered throughout different tumor entities. pMED1 is phosphorylated by CDK7. Importantly, CDK7 and MED1 have been ascribed prognostic implications by various studies. However, their prognostic value in head and neck squamous-cell cancer (HNSCC) remains elusive. We applied immunohistochemical staining of CDK7 and pMED1 on our large and clinically well-characterized HNSCC tissue cohort comprising 419 patients. Software-aided quantification of staining intensity was performed as a measure of protein expression. The following results were linked to the clinicopathological features of our cohort and correlated in different tissue types (primary tumor, lymph node metastasis, distant metastasis, recurrence). Upregulation CDK7 was associated with worse 5-year overall survival as well as disease-free survival in HNSCC while being independent of other known prognostic factors such as p16-status. Also, CDK7 expression was significantly elevated in immune cell infiltrated tumors. In HNSCC CDK7 might serve as a novel prognostic marker to indicate the prognosis of patients. Furthermore, in vitro studies proved the feasibility of CDK7 inhibition with attenuating effects on cell proliferation underlining its remarkable translational potential for future therapeutic regimes.

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Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma

Cited by 80 publications

References 37 publications

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells

Role of the Transcription Factor FOSL1 in Organ Development and Tumorigenesis

CDK7 Predicts Worse Outcome in Head and Neck Squamous-Cell Cancer

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