lncRNA LINC00665 Stabilized by TAF15 Impeded the Malignant Biological Behaviors of Glioma Cells via STAU1-Mediated mRNA Degradation.

paper Cited Public

Authors: Ruan, Xuelei; Zheng, Jian; Liu, Xiaobai; Liu, Yunhui; Liu, Libo; Ma, Jun; He, Qianru; Yang, Chunqing; Wang, Di; Cai, Heng; Li, Zhen; Liu, Jing; Xue, Yixue
Year: 2020
Journal: Molecular therapy. Nucleic acids
PMID: 32464546
DOI: 10.1016/j.omtn.2020.05.003
PMCID: PMC7256440

Figure 1

TAF15 And LINC00665 Served as Tumor Suppressors in Glioma Cells(A) TAF15 protein levels in normal brain tissues (NBTs), low-grade glioma tissues (LGGTs) (grade I, n = 5; grade II, n = 5), and high-grade glioma tissues (HGGTs) (grade III. n = 5; grade IV, n = 5) (∗p < 0.05, ∗∗p < 0.01 versus NBTs group; #p < 0.05 versus LGGTs group). (B) TAF15 protein levels in human astrocytes (HAs) and the U251 and U87 groups (n = 3, each group; ∗p < 0.05, ∗∗p < 0.01 versus HAs group). (C) LINC00665 expression level in glioma tissues (∗∗p < 0.01 versus NBTs group). (D) RNA FISH assay to confirm subcellular location of LINC00665 in HA, U87, and U251 cells. Scale bars represent 20 μm. (E) LINC00665 expression level in normal HAs and glioma cell lines (n = 3, each group; ∗∗p < 0.01 versus HA group). (F) A CCK-8 assay was performed to test the effect of TAF15 and LINC00665 overexpression on proliferation in U87 and U251 cells. (G) Flow cytometry analysis of U87 and U251 cells with TAF15 and LINC00665 overexpression. (H) Quantification number of migration and invasion cells treated with upregulated TAF15 and LINC00665 (n = 3, each group; ∗p < 0.05 versus TAF15+-NC group; #p < 0.05 versus LINC00665+-NC group; ▲p < 0.05 versus TAF15+ group; ▪p < 0.05 versus LINC00665+ group). Scale bars represent 200 μm.

Figure 2

TAF15 Stabilized LINC00665 and MTF1 Played an Oncogenic Role in Glioma Cells(A) Relative expression of LINC00665 in glioma cells treated with TAF15 overexpression (n = 3, each group; ∗p < 0.05 versus TAF15+-NC group). (B and C) An RNA-IP assay (B) and RNA pull-down assay (C) were used to identify LINC00665 in the TAF15 complex. LINC00665 enrichment was measured using quantitative real-time PCR (n = 3, each group; ∗∗p < 0.01 versus anti-IgG group). (D) Expression level of nascent LINC00665 was measured by quantitative real-time PCR (n = 3, each group; p > 0.05 versus TAF15+-NC group). (E) The half-life of LINC00665 in the U87 glioma cells (left) and U251 glioma cells (right) treated with TAF15 overexpression. (F) MTF1 expression levels in NBTs, LGGTs, and HGGTs are shown (∗∗p < 0.01 versus NBTs group; ##p < 0.01 versus LGGTs group). (G) MTF1 expression levels in HA, U87, and U251 cell lines are shown (n = 3, each group; ∗∗p < 0.01 versus HA group). (H) A CCK-8 assay was used to measure the effect of MTF1 on the proliferation of glioma cells. (I) The apoptotic percentages of glioma cells were detected with MTF1 upregulation or downregulation. (J) A transwell assay was used to measure the effect of MTF1 on cell migration and invasion of U87 and U251 glioma cells (n = 3, each group; ∗p < 0.05 versus MTF1+-NC group; #p < 0.05 versus MTF1−-NC group). Scale bars represent 200 μm.

Figure 3

LINC00665 Destabilized MTF1 mRNA by Interacting with STAU1, thus Regulating Glioma Cell Malignant Progression(A and B) Quantitative real-time PCR (A) and western blot (B) were applied to test expression levels of MTF1 (∗p < 0.05 versus LINC00665+-NC group; #p < 0.05 versus STAU1−-NC group; ▲p < 0.05 versus LINC00665+ group). (C) LINC00665 and MTF1 could bind to STAU1 protein, respectively. Both relative enrichment levels of LINC00665 and MTF1 were measured using quantitative real-time PCR (n = 3, each group; ∗∗p < 0.01 versus anti-IgG group). (D) The predicted LINC00665 binding site in MTF1 (MTF1-3′ UTR-WT) and the designed mutant sequence (MTF1-3′ UTR-Mut) are shown (left). Luciferase reporter gene assays of HEK293T cells are shown (right) (n = 3, each group; ∗p < 0.05 versus MTF1-3′ UTR-WT + LINC00665-NC group). (E) Remaining MTF1 mRNA (%) at the different actinomycin D treatment times in control group, LINC00665+-NC group, and LINC00665+ group. (F) Remaining MTF1 mRNA (%) in control group, STAU1−-NC group, and STAU1− group. (G–I) CCK-8 (G), flow cytometry (H), and transwell assays (I) were used to assess the proliferation, apoptosis, migration, and invasion capacity of U87 and U251 glioma cells (n = 3, each group; ∗p < 0.05 versus control group; #p < 0.05 versus LINC00665+ + MTF1+ group; ▲p < 0.05 versus LINC00665− + MTF1− group). Scale bars represent 200 μm.

Figure 4

Knockdown of YY2 Inhibited Malignant Progression of Glioma Cells(A) YY2 expression levels in NBTs and glioma tissues are shown (∗∗p < 0.01 versus NBTs group; #p < 0.05 versus LGGTs group). (B) YY2 expression levels in HA, U87, and U251 cell lines are shown (n = 3, each group; ∗p < 0.05, ∗∗p < 0.01 versus HA group). (C) A CCK-8 assay was used to measure the effect of YY2 on the proliferation of glioma cells. (D) The apoptotic percentages of glioma cells were detected with YY2 upregulation or downregulation. (E) A transwell assay was used to measure the effect of YY2 on cell migration and invasion of U87 and U251 glioma cells (n = 3, each group; ∗p < 0.05 versus YY2+-NC group; #p < 0.05 versus YY2−-NC group). Scale bars represent 200 μm. (F and G) Quantitative real-time PCR (F) and western blot (G) were performed to observe YY2 expression variation (n = 3, each group; ∗p < 0.05 versus LINC00665+-NC group; #p < 0.05 versus STAU1−-NC group; ▲p < 0.05 versus LINC00665+ group).

Figure 5

YY2 Was Destabilized by LINC00665 via the SMD Pathway Regulating Malignant Progression of Glioma(A) The predicted LINC00665 binding site in YY2 (YY2-3′ UTR-WT) and the designed mutant sequence (YY2-3′ UTR-Mut) are shown (left). Luciferase reporter gene assays of HEK293T cells are shown (right) (n = 3, each group; ∗p < 0.05 versus YY2-3′ UTR-WT + LINC00665-NC group). (B) RNA-IP assay was conducted to determine the association among LINC00665, YY2, and STAU1 (n = 3, each group; ∗∗p < 0.01 versus anti-IgG group). (C) The half-life of YY2 in the control group, LINC00665+-NC group, and LINC00665+ group. (D) The half-life of YY2 in the control group, STAU1−-NC group, and STAU1− group. (E–G) CCK-8 (E), flow cytometry (F), and transwell assays (G) were conducted to determine the effect of co-transfection of LINC00665 and YY2 on the proliferation, apoptosis, migration, and invasion of glioma cells (n = 3, each group; ∗p < 0.05 versus control group; #p < 0.05 versus LINC00665+ + YY2+ group; ▲p < 0.05 versus LINC00665− + YY2− group). Scale bars represent 200 μm.

Figure 6

GTSE1 Was Upregulated in Glioma Cells, and Knockdown of GTSE1 Inhibited Malignant Biological Behaviors(A) GTSE1 expression levels in NBTs, LGGTs, and HGGTs are shown (∗∗p < 0.01 versus NBTs group; ##p < 0.01 versus LGGTs group). (B) GTSE1 expression levels in HA, U87, and U251 cell lines are shown (n = 3, each group; ∗∗p < 0.01 versus HA group). (C) CCK-8 assay was performed to assess the effect of GTSE1 knockdown on the proliferation of glioma cells. (D) The ratio of apoptotic glioma cells were detected with GTSE1 downregulation. (E) Number of migrated and invaded glioma cells was counted to represent the effect of GTSE1 inhibition on cell migration and invasion (n = 3, each group; ∗p < 0.05 versus GTSE1−-NC group). Scale bars represent 200 μm. (F) The expression level of GTSE1 mRNA in glioma cells treated with MTF1 variation. (G) The expression level of GTSE1 protein in glioma cells are shown (n = 3, each group; ∗p < 0.05 versus MTF1+-NC group; #p < 0.05 versus MTF1−-NC group). (H) The expression level of GTSE1 mRNA in glioma cells treated with YY2 variation. (I) The expression level of GTSE1 protein in glioma cells treated with YY2 variation (n = 3, each group; ∗p < 0.05 versus YY2+-NC group; #p < 0.05 versus YY2−-NC group).

Figure 7

MTF1 and YY2 Bound to the GTSE1 Promoter and Regulated the Expression Level of GTSE1(A) Schematic representation of the human GTSE1 promoter region 2,000 bp upstream of the transcription start site (TSS), which was designated as +1. Putative MTF1 binding site was indicated. PCR was conducted with the resulting precipitated DNA. (B) The change of GTSE1 mRNA expression level caused by LINC00665 and MTF1 variation. (C) The change of GTSE1 protein expression level caused by LINC00665 and MTF1 variation (n = 3, each group; ∗p < 0.05 versus control group; #p < 0.05 versus LINC00665+ + MTF1+ group; ▲p < 0.05 versus LINC00665− + MTF1− group). (D) YY2 bound to the promoter of GTSE1 in glioma cells. Three putative YY2 binding sites were indicated. PCR was conducted with the resulting precipitated DNA. (E) The change of GTSE1 mRNA expression level caused by LINC00665 and YY2 variation. (F) The change of GTSE1 protein expression level caused by LINC00665 and YY2 variation (n = 3, each group; ∗p < 0.05 versus control group; #p < 0.05 versus LINC00665+ + YY2+ group; ▲p < 0.05 versus LINC00665− + YY2− group).

Figure 8

In Vivo Study and the Schematic Picture of the Mechanisms in Our Study(A) Nude mice carrying tumors from respective groups are shown. The sample tumors from respective groups are shown. (B) Tumor volume was calculated every 4 days after injection, and tumors were excised after 44 days (∗p < 0.05 versus control group; #p < 0.05 versus TAF15+ group; ▲p < 0.05 versus LINC00665+ group; ▪p < 0.05 versus MTF1+ group; ●p < 0.05 versus YY2+ group). (C) The survival curves of nude mice injected into the right striatum. (D) The schematic picture of the mechanism in which TAF15 combined with LINC00665, thus enhancing the degradation of MTF1 and YY2 mRNA via the SMD pathway in glioma cells. Ter, translation termination codon.

#	Section	Preview
20	Results — MTF1 and YY2 Bound to the GTSE1 Promoter Region and Induced Its Expression	DBTSS and JASPAR indicated that the GTSE1 promoter contains three putative binding sites for YY2,…
21	Results — MTF1 and YY2 Bound to the GTSE1 Promoter Region and Induced Its Expression	Furthermore, we verified that GTSE1 overexpression might rescue the LINC00665-mediated reduction in…
22	Results — MTF1 or YY2 Knockdown Combined with TAF15 and LINC00665 Overexpression Reduced Tumor Growth In Vivo	Finally, we evaluated the influence of these four factors in vivo using a nude mice glioma xenograft…
23	Discussion	In this study, we identified the role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in the malignant…
24	Discussion	TAF15 belongs to the FET family of conserved RBPs that play essential roles in the tumorigenesis of…
25	Discussion	Our study revealed that LINC00665 is downregulated in glioma tissues and cells, and overexpression…
26	Discussion	Our previous studies provided some insight into the regulatory mechanisms of various lncRNAs on the…
27	Discussion	lncRNAs regulate downstream gene functions, including the well-established regulation of the…
28	Discussion	and activating the SMD pathway.46, 47, 48 Using the bioinformatics software RepeatMasker and…
29	Discussion	A previous immunohistochemistry study showed that MTF1 expression is relatively high in human…
30	Discussion	Since the promoter region of GTSE1 harbors diverse putative binding sites, a ChIP assay was used to…
31	Discussion	In summary, our study verified that TAF15 and LINC00665 are downregulated in glioma tissues and…
32	Materials and Methods — Human lncRNA Microarrays	Samples including normal human astrocytes and U251 and U87 glioma cells, which were prepared for…
33	Materials and Methods — Cell Culture and Human Tissue Samples	We purchased human U251 and U87 glioma cells and the HEK293T cell line from the China Academy of…
34	Materials and Methods — RNA Extraction and Quantitative Real-Time PCR	Our study used TRIzol reagent (Life Technologies, USA) to extract total RNA from cells and tissues.…
35	Materials and Methods — Western Blot	Total protein of cells was extracted with a radioimmunoprecipitation assay (RIPA) buffer containing…
36	Materials and Methods — Cell Transfection	TAF15 full-length plasmid TAF15+, MTF1 full-length plasmid MTF1+, YY2 full-length plasmid YY2+, and…
37	Materials and Methods — RNA FISH Assays	Alexa Fluor 555-labeled LINC00665 probes and Alexa Fluor 488-labeled MTF1 and YY2 probes were…
38	Materials and Methods — Reporter Vector Construction and Luciferase Reporter Gene Assays	The WT or Mut luciferase expression vector of the putative binding site in MTF1 and YY2 mRNA 3′…
39	Materials and Methods — RNA-IP Assay	Briefly, glioma cells were transfected with WT LINC00665 or Mut LINC00665 plasmid with the putative…

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Long non-coding RNA SNHG4 enhances RNF14 mRNA stability to promote the progression of colorectal cancer by recruiting TAF15 protein.	Lv L et al.	—	2023	→
m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma.	Zheng WH et al.	—	2023	→
Prognostic and clinicopathological values of LINC00665 in cancers: a systematic review and China population-based meta-analysis.	Jin Z et al.	—	2023	→
RNA alternative splicing impacts the risk for alcohol use disorder	Liu Y et al.	—	2023	—
RNA alternative splicing impacts the risk for alcohol use disorder.	Li R et al.	—	2023	→
TAF15 promotes cell proliferation, migration and invasion of gastric cancer via activation of the RAF1/MEK/ERK signalling pathway.	Tang L et al.	—	2023	→
TAF15 regulates the BRD4/GREM1 axis and activates the gremlin-1-NF-κB pathway to promote OA progression.	Du X et al.	—	2023	→
The prognostic value and immune landscaps of m6A/m5C-related lncRNAs signature in the low grade glioma.	Li R et al.	—	2023	→
A Concise Review on Dysregulation of LINC00665 in Cancers.	Ghafouri-Fard S et al.	—	2022	→
circVMA21 combining with TAF15 stabilizes SOCS3 mRNA to relieve septic lung injury through regulating NF-κB activation.	Zhu ZG et al.	—	2022	→
Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients.	Zhang G et al.	—	2022	→
Identification of Ferroptosis-Related Biomarkers for Prognosis and Immunotherapy in Patients With Glioma.	Shi J et al.	—	2022	→
LINC00624/TEX10/NF-κB axis promotes proliferation and migration of human prostate cancer cells.	Zhou J et al.	—	2022	→
LINC00665: An Emerging Biomarker for Cancer Diagnostics and Therapeutics.	Zhong C et al.	—	2022	→
LncRNA HOTTIP facilitates osteogenic differentiation in bone marrow mesenchymal stem cells and induces angiogenesis via interacting with TAF15 to stabilize DLX2.	Zeng X et al.	—	2022	→
Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention.	Mirzaei S et al.	—	2022	→
Phosphomimicry on STAU1 Serine 20 Impairs STAU1 Posttranscriptional Functions and Induces Apoptosis in Human Transformed Cells.	Gonzalez Quesada Y et al.	—	2022	→
Proteomics and metabolomics approach in adult and pediatric glioma diagnostics.	Pienkowski T et al.	—	2022	→
RBM47/SNHG5/FOXO3 axis activates autophagy and inhibits cell proliferation in papillary thyroid carcinoma.	Qin Y et al.	—	2022	→
Tetramethylpyrazine Inhibits the Proliferation and Invasion of Glioma Cells by Regulating the UBL7-AS1/miR-144-3p Pathway.	Liang R et al.	—	2022	→
The Biological and Molecular Function of LINC00665 in Human Cancers.	Zhang C et al.	—	2022	→
The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma.	Wang W et al.	—	2022	→
The Emerging Roles of LINC00665 in Human Cancers.	Zhu J et al.	—	2022	→
Bioinformatic Analyses Identify a Prognostic Autophagy-Related Long Non-coding RNA Signature Associated With Immune Microenvironment in Diffuse Gliomas.	Xu S et al.	—	2021	→
GLIDR promotes the progression of glioma by regulating the miR-4677-3p/MAGI2 axis.	Yu Q et al.	—	2021	→
High Level of Staufen1 Expression Confers Longer Recurrence Free Survival to Non-Small Cell Lung Cancer Patients by Promoting THBS1 mRNA Degradation.	Bonnet-Magnaval F et al.	—	2021	→
Hypoxia-Related lncRNA Correlates With Prognosis and Immune Microenvironment in Lower-Grade Glioma.	Xu S et al.	—	2021	→
LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization.	Wang J et al.	—	2021	→
LncRNA GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 to promote wound healing in diabetic foot ulcers.	Peng WX et al.	—	2021	→
Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis.	Lu M et al.	—	2021	→
Long non-coding RNA (LncRNA) SNHG7/ Eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) involves in the malignant events of ovarian cancer cells with paclitaxel resistant.	Zhang J et al.	—	2021	→
Non-Coding RNAs and Brain Tumors: Insights Into Their Roles in Apoptosis.	Tamtaji OR et al.	—	2021	→
Potential biomarkers of childhood brain tumor identified by proteomics of cerebrospinal fluid from extraventricular drainage (EVD).	Bruschi M et al.	—	2021	→
Roles of Long Noncoding RNAs in Conferring Glioma Progression and Treatment.	Qin J et al.	—	2021	→
The Long Noncoding RNA LINC00665 Facilitates c-Myc Transcriptional Activity <i>via</i> the miR-195-5p MYCBP Axis to Promote Progression of Lung Adenocarcinoma.	Wang A et al.	—	2021	→
The multifunctional RNA-binding protein Staufen1: an emerging regulator of oncogenesis through its various roles in key cellular events.	Almasi S et al.	—	2021	→
Immune-Related lncRNA Risk Signatures Predict Survival of IDH Wild-Type and MGMT Promoter Unmethylated Glioblastoma.	Li X et al.	—	2020	→
Oncogenic roles of lncRNA BLACAT1 and its related mechanisms in human cancers.	Han W et al.	—	2020	→