Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy

Shaath, Hibah; Vishnubalaji, Radhakrishnan; Elango, Ramesh; Khattak, Shahryar; Alajez, Nehad M.

doi:10.1038/s41420-020-00383-y

Cited by 56 publications

(45 citation statements)

References 45 publications

(54 reference statements)

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“…MALAT1 was the most downregulated lncRNA in response to DNMTi of TNBC. Our recent data implicated MALAT1 in TNBC resistance to neoadjuvant chemotherapy where we showed CRISPR-Cas9 mediated MALAT1 promoter deletion to reduce CFU and enhance sensitivity of TNBC cells to chemotherapy, hence corroborating data from current study [ 73 ].…”

Section: Discussionsupporting

confidence: 90%

Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition

et al. 2021

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Background DNA methylation plays a crucial role in multiple cellular processes such as gene regulation, chromatin stability, and genetic imprinting. In mammals, DNA methylation is achieved by DNA methyltransferases (DNMTs). A number of studies have associated alterations in DNMT activity to tumorigenesis; however, the exact role of DNMTs in shaping the genome in triple negative breast cancer (TNBC) is still being unraveled. Methods In the current study, we employed two DNMT inhibitors (Decitabine and 5-Azacytidine), two TNBC models (MDA-MB-231 and BT-549) and whole transcriptome RNA-Seq and characterized the transcriptional alterations associated with DNMT inhibition. Colony forming unit (CFU), flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. Ingenuity pathway analysis (IPA) was used for network and pathway analyses. Results Remarkably, DNMT inhibition induced the expression of genes involved in endoplasmic reticulum response to stress, response to unfolder protein, as well as cobalamin metabolic processes. In contrast, suppression of cellular processes related to cell cycle and mitosis were hallmarks of DNMT inhibition. Concordantly, DNMT inhibition led to significant inhibition of TNBC cell proliferation, G2-M cell cycle arrest and induction of cell death. Mechanistically, DNMT inhibition activated TP53, NUPR1, and NFkB (complex) networks, while RARA, RABL6, ESR1, FOXM1, and ERBB2 networks were suppressed. Our data also identified the long noncoding RNA (lncRNA) transcriptional portrait associated with DNMT inhibition and identified 25 commonly upregulated and 60 commonly downregulated lncRNAs in response to Decitabine and 5-Azacytidinec treatment in both TNBC models. TPT1-AS1 was the most highly induced (6.3 FC), while MALAT1 was the most highly suppressed (− 7.0 FC) lncRNA in response to DNMT inhibition. Conclusions Taken together, our data provides a comprehensive view of transcriptome alterations in the coding and noncoding transcriptome in TNBC in response to DNMT inhibition.

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Section: Discussionsupporting

confidence: 90%

Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition

et al. 2021

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“…MALAT1 was expressed more highly than any other lncRNA in both T1 and T2, which is in agreement with the literature [10]. MALAT1 has been shown to be a prognostic marker in TNBC [49], and implicated in therapeutic resistance [50] and metastasis in breast cancer [51]. It appears to affect the malignant phenotype by chromatin binding, and as a splicing modulator [52].…”

Section: Discussionsupporting

confidence: 85%

Single-Cell RNA-Seq Reveals Heterogeneous lncRNA Expression in Xenografted Triple-Negative Breast Cancer Cells

Pinkney

Black

Diermeier

2021

Biology

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Breast cancer is the most commonly diagnosed cancer in the world, with triple-negative breast cancer (TNBC) making up 12% of these diagnoses. TNBC tumours are highly heterogeneous in both inter-tumour and intra-tumour gene expression profiles, where they form subclonal populations of varying levels of aggressiveness. These aspects make it difficult to study and treat TNBC, requiring further research into tumour heterogeneity as well as potential therapeutic targets and biomarkers. Recently, it was discovered that the majority of the transcribed genome comprises non-coding RNAs, in particular long non-coding RNAs (lncRNAs). LncRNAs are transcripts of >200 nucleotides in length that do not encode a protein. They have been characterised as regulatory molecules and their expression can be associated with a malignant phenotype. We set out to explore TNBC tumour heterogeneity in vivo at a single cell level to investigate whether lncRNA expression varies across different cells within the tumour, even if cells are coming from the same cell line, and whether lncRNA expression is sufficient to define cellular subpopulations. We applied single-cell expression profiling due to its ability to capture expression signals of lncRNAs expressed in small subpopulations of cells. Overall, we observed most lncRNAs to be expressed at low, but detectable levels in TNBC xenografts, with a median of 25 lncRNAs detected per cell. LncRNA expression alone was insufficient to define a subpopulation of cells, and lncRNAs showed highly heterogeneous expression patterns, including ubiquitous expression, subpopulation-specific expression, and a hybrid pattern of lncRNAs expressed in several, but not all subpopulations. These findings reinforce that transcriptionally defined tumour cell subpopulations can be identified in cell-line derived xenografts, and uses single-cell RNA-seq (scRNA-seq) to detect and characterise lncRNA expression across these subpopulations in xenografted tumours. Future studies will aim to investigate the spatial distribution of lncRNAs within xenografts and patient tissues, and study the potential of subclone-specific lncRNAs as new therapeutic targets and/or biomarkers.

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“…Recent studies revealed that lncRNAs acted as a key regulator in the pathogenesis, progression, and phenotype development of breast cancer (32). Growing data delineated LncRNAs dysregulated in breast cancer (33)(34)(35)(36)(37). As previously described, lncRNA FGD5-AS1 participated as an essential mediator in various cancer.…”

Section: Discussionmentioning

confidence: 71%

LncRNA FGD5-AS1 Facilitates the Radioresistance of Breast Cancer Cells by Enhancing MACC1 Expression Through Competitively Sponging miR-497-5p

Lei

Chen

et al. 2021

Front. Oncol.

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BackgroundLncRNA-FGD5-AS1, as an oncogene, participates in the development and progress of various cancers. However, the exact role and the molecular mechanisms by which FGD5-AS1 regulates radiosensitivity in breast cancer (BC) remains largely unknown.MethodsWe used X-Ray weekly-dose-increase method to establish radiation-resistance cell lines. Bioinformatics tools analyze the expression of FGD5-AS1 in breast cancer tissue and evaluated the relationship between FGD5-AS1 and clinic-pathological features. CCK-8 and colony formation were used to analyze cell proliferation. Western blotting and qPCR were applied to detect protein and gene expression, respectively. RNA interference was used to knock down the endogenous gene expression. Luciferase reporter system and immunoprecipitates were applied to verify the target of FGD5-AS1.ResultFGD5-AS1 was overexpressed in BC tissues and radiation-resistance cell lines. Higher levels of FGD5-AS1 predicted poorer clinical characteristics and prognosis. Loss-of-function FGD5-AS1 sensitized BC cells to X-ray, meanwhile, the cell gained radiation-resistance when exogenous FGD5-AS1 was expressed. FGD5-AS1 depletion arrested cells at G0/G1 and triggers cell apoptosis. The starBase database (ENCORI), predicted binding site of miR-497-5p in FGD5-AS1 sequence, and luciferase reporter system and immunoprecipitates verified miR-497-5p was the target of FGD5-AS1. Furthermore, MACC1 was predicted and verified as the target of miR-497-5p. Loss-of-function FGD5-AS1 sensitized ionizing radiation was rescued by the up-regulation of MACC1 and the inhibition of miR-497.ConclusionFGD5-AS1 displays an oncogene profile in CRC; patients with high expression of FGD5-AS1 should benefit less from radiotherapy and need a more frequent follow-up. Besides, FGD5-AS1 may be a potential therapeutic target for CRC.

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Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy

Cited by 56 publications

References 45 publications

Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition

Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition

Single-Cell RNA-Seq Reveals Heterogeneous lncRNA Expression in Xenografted Triple-Negative Breast Cancer Cells

LncRNA FGD5-AS1 Facilitates the Radioresistance of Breast Cancer Cells by Enhancing MACC1 Expression Through Competitively Sponging miR-497-5p

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