Dataset Information

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.

ABSTRACT: Breast cancer is a leading cause of cancer-related deaths among women, and current therapies benefit only a subset of these patients. Here, we show that ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in patient-derived breast cancer samples, and UBE2T overexpression predicts poor prognosis. We demonstrate that the transcription factor AP-2 alpha (TFAP2A) is necessary for the overexpression of UBE2T in breast cancer cells, and UBE2T inhibition suppresses breast cancer tumor growth in cell culture and in mice. RNA sequencing analysis identified interferon alpha-inducible protein 6 (IFI6) as a key downstream mediator of UBE2T function in breast cancer cells. Consistently, UBE2T inhibition downregulated IFI6 expression, promoting DNA replication stress, cell cycle arrest, and apoptosis and suppressing breast cancer cell growth. Breast cancer cells with IFI6 inhibition displayed similar phenotypes as those with UBE2T inhibition, and ectopic IFI6 expression in UBE2T-knockdown breast cancer cells prevented DNA replication stress and apoptosis and partly restored breast cancer cell growth. Furthermore, UBE2T inhibition enhanced the growth-suppressive effects of DNA replication stress inducers. Taken together, our study identifies UBE2T as a facilitator of breast cancer tumor growth and provide a rationale for targeting UBE2T for breast cancer therapies.

SUBMITTER: Dutta R

PROVIDER: S-EPMC9629447 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.

Dutta Roshan R Guruvaiah Praveen P Reddi Kiran Kumar KK Bugide Suresh S Reddy Bandi Dhana Sekhar DS Edwards Yvonne J K YJK Singh Kamaljeet K Gupta Romi R

NAR cancer 20221102 4

Breast cancer is a leading cause of cancer-related deaths among women, and current therapies benefit only a subset of these patients. Here, we show that ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in patient-derived breast cancer samples, and UBE2T overexpression predicts poor prognosis. We demonstrate that the transcription factor AP-2 alpha (TFAP2A) is necessary for the overexpression of UBE2T in breast cancer cells, and UBE2T inhibition suppresses breast cancer tumor growth in c ...[more]

PMID: 36338541

Similar Datasets

Project description:BackgroundIntratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive.Methods16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8+ T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay.ResultsWe found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8+ T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8+ T cell infiltration, thus promoting tumor immune escape.ConclusionsThis study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.

Project description:Necroptosis is a form of regulated necrosis and is executed by MLKL when MLKL is engaged in triggering the rupture of cell plasma membrane. MLKL activation also leads to the protease, ADAMs-mediated ectodomain shedding of cell surface proteins of necroptotic cells. Tumor necroptosis often happens in advanced solid tumors, and blocking necroptosis by MLKL deletion in breast cancer dramatically reduces tumor metastasis. It has been suggested that tumor necroptosis affects tumor progression through modulating the tumor microenvironment. However, the exact mechanism by which tumor necroptosis promotes tumor metastasis remains elusive. Here, we report that the ectodomain shedding of cell surface proteins of necroptotic cells is critical for the promoting effect of tumor necroptosis in tumor metastasis through inhibiting the anti-tumor activity of T cells. We found that blocking tumor necroptosis by MLKL deletion led to the dramatic reduction of tumor metastasis and significantly elevated anti-tumor activity of tumor-infiltrating and peripheral blood T cells. Importantly, the increased anti-tumor activity of T cells is a key cause for the reduced metastasis as the depletion of CD8+ T cells completely restored the level of metastasis in the Mlkl KO mice. Interestingly, the levels of some soluble cell surface proteins including sE-cadherin that are known to promote metastasis are also dramatically reduced in MLKL null tumors/mice. Administration of ADAMs pan inhibitor reduces the levels of soluble cell surface proteins in WT tumors/mice and leads to the dramatic decrease in metastasis. Finally, we showed the sE-cadherin/KLRG1 inhibitory receptor is the major pathway for necroptosis-mediated suppression of the anti-tumor activity of T cells and the promotion of metastasis. Hence, our study reveals a novel mechanism of tumor necroptosis-mediated promotion of metastasis and suggests that tumor necroptosis and necroptosis-activated ADAMs are potential targets for controlling metastasis.

Project description:The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes and organogenesis pathways. The four family members of this PP family possess transcriptional activation and phosphatase functions, with serine/threonine and tyrosine phosphatase domains. EYA4 has been associated with several human cancers, with tumor-suppressing and tumor-promoting roles. However, EYA4 is the least well-characterized member of this unique family of PP, with its biological functions and molecular mechanisms in cancer progression, particularly in breast cancer, still largely unknown. In the present study, we found that the over-expression of EYA4 in breast tissue leads to an aggressive and invasive breast cancer phenotype, while the inhibition of EYA4 reduced tumorigenic properties of breast cancer cells in vitro and in vivo. Cellular changes downstream of EYA4, including cell proliferation and migration, may explain the increased metastatic power of breast cancer cells over-expressing EYA4. Mechanistically, EYA4 prevents genome instability by inhibiting the accumulation of replication-associated DNA damage. Its depletion results in polyploidy as a consequence of endoreplication, a phenomenon that can occur in response to stress. The absence of EYA4 leads to spontaneous replication stress characterized by the activation of the ATR pathway, sensitivity to hydroxyurea, and accumulation of endogenous DNA damage as indicated by increased γH2AX levels. In addition, we show that EYA4, specifically its serine/threonine phosphatase domain, plays an important and so far, unexpected role in replication fork progression. This phosphatase activity is essential for breast cancer progression and metastasis. Taken together, our data indicate that EYA4 is a novel potential breast cancer oncogene that supports primary tumor growth and metastasis. Developing therapeutics aimed at the serine/threonine phosphatase activity of EYA4 represents a robust strategy for killing breast cancer cells, to limit metastasis and overcome chemotherapy resistance caused by endoreplication and genomic rearrangements.

Dataset Information

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.

Publications

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets