LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA

Tang, Jianming; Zhong, Guang-sheng; Zhang, Haibo; Yu, Bo; Wei, Fangqiang; Luo, Liming; Kang, Yubin; Wu, Jianhui; Jiang, Jianhui; Li, Yucheng; Wu, Shuqiang; Jia, Yongshi; Liang, Xiaodong; Bi, Aihong

doi:10.1038/s41419-018-1220-7

Cited by 71 publications

(61 citation statements)

References 32 publications

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“…For example, DANCR is able to upregulate CTNNB1 in HCC [17], and activate AKT pathway in osteosarcoma [18]. Consistent with these findings, DANCR is upregulated in a variety of cancer types including nasopharyngeal carcinoma, bladder cancer, breast cancer, prostate and ovarian cancer [30][31][32][33]. These studies suggest that a major mechanism for DANCR to regulate gene expression is to function as a microRNA sponge, i.e., competitive endogenous RNA mechanism [34].…”

Section: Discussionmentioning

confidence: 55%

“…In addition, DANCR can increase HIF-1α mRNA stability through interacting with the NF90/NF45 complex [30]; it activates IL-11-STAT3 signaling and increases cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA [31]. In breast cancer, DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA [33]. However, little is known about the function of DANCR in pancreatic cancer, and in particular, it is not known whether DANCR is subject to m6A modification.…”

Section: Discussionmentioning

confidence: 99%

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IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader

et al. 2019

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The major function of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is to regulate cell metabolism. However, emerging evidence indicates that IGF2BP2 plays a role in cancer, but the underlying mechanism is largely unknown. Here we showed that upregulation of IGF2BP2 is associated with poor outcomes of pancreatic cancer patients and suppression of IGF2BP2 inhibits cell proliferation. We further showed that IGF2BP2 regulates lncRNA DANCR. Ectopic expression IGF2BP2 enhances, whereas knockdown (KD) or knockout (KO) of IGF2BP2 suppresses DANCR expression. Moreover, in vivo RNA precipitation and reciprocal RNA immunoprecipitation revealed that IGF2BP2 interacts with DANCR. DANCR promotes cell proliferation and stemness-like properties. Experiments with xenograft models revealed that while ectopic expression of DANCR promotes, DANCR KO suppresses tumor growth. Mechanistically, DANCR is modified at N6-methyladenosine (m6A) and mutagenesis assay identified that adenosine at 664 of DANCR is critical to the interaction between IGF2BP2 and DANCR where IGF2BP2 serves a reader for m6A modified DANCR and stabilizes DANCR RNA. Together, these results suggest that DANCR is a novel target for IGF2BP2 through m6A modification, and IGF2BP2 and DANCR work together to promote cancer stemness-like properties and pancreatic cancer pathogenesis.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader

et al. 2019

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“…RIP and RNA pull-down assays were performed as we previously described [44]. Antibodies used for RIP are displayed as follows: WDR5 (#13105,1:50, Cell Signaling Technology), KAT2B (#3378, 1:50, Cell Signaling Technology), KAT5 (#12058,1:50, Cell Signaling Technology), KAT8 (#46862, 1:50, Cell Signaling Technology), KAT6A (ABP59003, 1:100, Abbkine), and KAT2A (#3305S, 1:50, Cell Signaling Technology).…”

Section: Chip-qpcrmentioning

confidence: 99%

The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α

et al. 2019

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Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.

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“…LncRNA NRAD1 was regulated by ALDH1A3 and was a therapeutic target for TNBC for its regulation of gene expression and effect on cancer cell survival 95 . LncRNA DANCR enhanced PI3K/AKT signals and TNBC proliferation by binding to RXRA and increasing its serine 49/78 phosphorylation to activate PIK3CA transcription 96 …”

Section: Long Non‐coding Rnasmentioning

confidence: 99%

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

et al. 2020

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Triple‐negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with negativity for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Non‐coding RNAs (ncRNAs) make up most of the transcriptome and are widely present in eukaryotic cells. In recent years, emerging evidence suggests that ncRNAs, mainly microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs), play prominent roles in the tumorigenesis and development of TNBC, but the functions of most ncRNAs have not been fully described. In this review, we systematically elucidate the general characteristics and biogenesis of miRNAs, lncRNAs and circRNAs, discuss the emerging functions of these ncRNAs in TNBC and present future perspectives in clinical practice.

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LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA

Cited by 71 publications

References 32 publications

IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader

IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader

The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

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