Super enhancer associated <i>RAI14</i> is a new potential biomarker in lung adenocarcinoma

Yuan, Chongze; Hu, Hong; Kuang, Muyu; Chen, Zongwei; Tao, Xiaoting; Fang, Shengjian; Sun, Yihua; Zhang, Yawei; Chen, Hai Quan

doi:10.18632/oncotarget.22165

Cited by 18 publications

(24 citation statements)

References 51 publications

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“…Tippens and colleagues (15) reported that enhancers and promoters harbored more similarities than expected. Promoters capable of bidirectional transcription are associated with enhancer activity (14), and the transcribed enhancer RNAs have been proposed to contribute to enhancer activity (24)(25)(26). The bidirectional transcription ability has been verified by luciferase activity and the chromatin state segmentation from ENCODE also predicted this promoter region with enhancer potential.…”

Section: Discussionmentioning

confidence: 94%

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

et al. 2019

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Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS.NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.Significance: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

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Section: Discussionmentioning

confidence: 94%

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

et al. 2019

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“… 12 – 14 SEs are reported to be enriched at oncogenes in cancer cells, which are generated and activated through chromosomal rearrangements, focal amplification, and upregulation of transcription factors. 11 , 14 , 15 As confirmed by multiple research works, the upregulation of SE is involved in the tumor pathogenesis. 16 Besides that, SEs in cancer cells are more susceptible to perturbation as compared with the typical enhancer, which leads to a more pronounced impairment of the expression of SEs-related genes.…”

Section: Introductionmentioning

confidence: 79%

“…RAI14 has been proved as an SE associated gene that is upregulated in lung adenocarcinoma and impacts the cell proliferation. 11 To the best of our understanding, no data are available to indicate the relationship between RAI14 and gastric cancer. In our study, we observed that the expression of RAI14 was upregulated in gastric cancer and the RAI14 expression level was correlated with the prognosis of gastric cancer patients, indicating that RAI14 might be involved in progression of gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

“… 9 , 10 Recent studies highlight that RAI14 is a super enhancer (SE)-related gene that is upregulated in non-small-cell lung cancer (NSCLC) cell A549 and a portion of tumor tissues (43.66%, 32/71), and functions as a potential bio-marker for the patients with lung adenocarcinoma. 11 SE is a large cis-regulatory element enhancing the expression of crucial genes that could define cell identity, in addition to playing a pivotal role in the process of development and cancer. 12 – 14 SEs are reported to be enriched at oncogenes in cancer cells, which are generated and activated through chromosomal rearrangements, focal amplification, and upregulation of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of RAI14 suppresses the progression of gastric cancer

Chen¹,

Aihemaiti²,

Zhang³

et al. 2018

OTT

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BackgroundRetinoic acid induced 14 (RAI14), also known as NORPEG, is reported as being deregulated in non-small-cell lung cancer, together with having involvement in its cell proliferation as a super enhancer related gene.PurposeThe objective of this study was to investigate the role of RAI14 in the progression and metastasis of gastric cancer and explore the associated mechanism.Materials and methodsGEPIA database was used to analyze the expression of RAI14 in gastric cancer. MNK45 and AGS cells were transfected with siRNA-RAI14 to block the expression of RAI14. Cell Counting Kit 8 and colony formation assays were performed to measure cell proliferation. Cell migration and invasion capacities was examined by transwell assay. Apoptosis rate was detected using flow cytometry, and the protein levels of apoptosis-related proteins was determined using Western blot assay. Reverse-transcription PCR assay was used to detect the expressions of RAB31.ResultsGene expression profiling interactive analysis revealed that RAI14 was substantially upregu-lated in gastric cancer and higher expression of RAI14 was associated with worse prognosis. We also observed that the knockdown of RAI14 by siRNA-RAI14 transfection suppressed growth capacity of MKN45 and AGS cells. Also, RAI14 knockdown inhibited migration and invasion of MKN45 and AGS cells in vitro. Moreover, RAI14 knockdown was observed to accelerate cell apoptosis via down-regulation of Bcl-2 and upregulation of Bax in MKN45 and AGS cells. Furthermore, downregulation of RAI14 inhibited the activation of Akt pathway, and activation of Akt by IGF-1 could restore the reduced proliferation induced by RAI14 knockdown. In addition, we found that RAI14 had a positive correlation with the RAB31 in gastric cancer by GEPIA reverse-transcription PCR and Western blot assays, and the reduced proliferation caused by RAI14 knockdown was restored by RAB31.ConclusionRAI14 knockdown inhibited proliferation, migration and invasion and promoted apoptosis by downregulating the Akt pathway in gastric cancer cells, and RAB31 might be a downstream target gene of RAI14, providing a novel sight into the molecular mechanism of RAI14 and a potential target for gastric cancer treatment.

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“…Instead, oncogenic activity was showed for RAI14, also named as novel retinal pigment epithelial cell gene (NORPEG), found to be aberrantly up-regulated in lung adenocarcinoma [249], and gastric cancer [250]. Recently, high expression of RAI14 in gastric cancer tissues, compared to matched normal tissues, was related to unfavourable patients' prognosis [251].…”

Section: Retinoid-inducible Gene 1 (Rig1) Hypermethylationmentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

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Super enhancer associated RAI14 is a new potential biomarker in lung adenocarcinoma

Cited by 18 publications

References 51 publications

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

Knockdown of RAI14 suppresses the progression of gastric cancer

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

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