cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

Chen, Zirong; Li, Jian Liang; Lin, Shuibin; Cao, Changqing; Gimbrone, Nicholas T.; Yang, Ruiqi; Fu, Danling; Carper, Miranda B.; Haura, Eric B.; Schabath, Matthew B.; Lu, Jianrong; Amelio, Antonio L.; Cress, W. Douglas; Kaye, Frederic J.; Wu, Lizi

doi:10.1172/jci85250

Cited by 171 publications

(183 citation statements)

References 55 publications

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“…Recently, several lncRNAs have been found to involve in NSCLC tumorigenesis, such as NEAT1, 30 TATDN1, 31 LINC00473, 32 AGAP2-AS1, 33 BC087858, 34 and LINC01133. 35 Sun et al .…”

Section: Introductionmentioning

confidence: 99%

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Long Intergenic Noncoding RNA 00511 Acts as an Oncogene in Non–small-cell Lung Cancer by Binding to EZH2 and Suppressing p57

Sun

et al. 2016

Molecular Therapy - Nucleic Acids

181

171

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Long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis. However, the function and mechanism of lncRNAs in human non–small-cell lung cancer (NSCLC) are still remaining largely unknown. Long intergenic noncoding RNA 00511 (LINC00511) has been found to be upregulated and acts as an oncogene in breast cancer, but little is known about its expression pattern, biological function and underlying mechanism in NSCLC. Herein, we identified LINC00511 as an oncogenic lncRNA by driving tumorigenesis in NSCLC. We found LINC00511 was upregulated and associated with oncogenesis, tumor size, metastasis, and poor prognosis in NSCLC. Moreover, LINC00511 affected cell proliferation, invasiveness, metastasis, and apoptosis in multiple NSCLC cell lines. Mechanistically, LINC00511 bound histone methyltransferase enhancer of zeste homolog 2 ((EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3), and acted as a modular scaffold of EZH2/PRC2 complexes, coordinated their localization, and specified the histone modification pattern on the target genes, including p57, and consequently altered NSCLC cell biology. Thus, LINC00511 is mechanistically, functionally, and clinically oncogenic in NSCLC. Targeting LINC00511 and its pathway may be meaningful for treating patients with NSCLC.

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“…Recently, several lncRNAs have been found to involve in NSCLC tumorigenesis, such as NEAT1, 30 TATDN1, 31 LINC00473, 32 AGAP2-AS1, 33 BC087858, 34 and LINC01133. 35 Sun et al .…”

Section: Introductionmentioning

confidence: 99%

“…30 LINC00473 is a nuclear lncRNA which expresses highly in NSCLC, elevated LINC00473 expression correlated with poor prognosis. 32 But up to date, the detail molecular mechanisms of lncRNAs in NSCLC are still needed to be further clarified.…”

Section: Introductionmentioning

confidence: 99%

Long Intergenic Noncoding RNA 00511 Acts as an Oncogene in Non–small-cell Lung Cancer by Binding to EZH2 and Suppressing p57

Sun

et al. 2016

Molecular Therapy - Nucleic Acids

181

171

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“…Since multiple AMPK family kinases (i.e. SIK2) can directly inhibit CRTCs, LKB1 loss therefore indirectly leads to CRTC1 hypophosphorylation and activation, and unregulated expression of oncogenic CRTC1 targets, such as glycosylphosphatidylinositol (GPI)-anchored metastasis-associated protein ( LYPD3 ), cyclooxygenase-2 ( COX-2 ), and the long coding RNA LINC00473 [65,67,68,75]. Dysregulation of LKB1/SIK2/CRTC1 pathway may therefore contribute to cancer progression.…”

Section: Crtcs and Cancer Proliferationmentioning

confidence: 99%

Deregulation of CRTCs in Aging and Age-Related Disease Risk

2017

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Advances in public health in the last century have seen a sharp increase in human life expectancy. With these changes have come increased incidence of age-related pathologies and health burdens in the elderly. Patient age is the biggest risk factor for multiple chronic conditions that often occur simultaneously within one individual. An alternative to disease centric therapeutic approaches is that of ‘geroscience’, which aims to define molecular mechanisms that link age to overall disease risk. One such mechanism is deregulation of CREB-regulated transcriptional coactivators, CRTCs. Initially identified for their role in modulating CREB transcription, the last five years has seen an expansion in knowledge of new cellular regulators and roles of CRTCs beyond CREB. CRTCs have been shown to modulate organismal aging in C. elegans and to impact age-related diseases in humans. Here, we discuss CRTC deregulation as a new driver of aging, and integrating link between age and disease risk.

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“…More importantly, numerous studies have revealed that aberrant lncRNA expression is involved in a wide range of human diseases, particularly cancers [16][17][18][19][20][21][22][23][24]. Mounting evidence in recent years has demonstrated that lncRNAs, such as MALAT1 [25], LINC00473 [26], AGAP2-AS1 [27] play crucial roles in NSCLC development and progression. LncRNA MALAT1 is a regulator of gene expression that governs the hallmarks of lung cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

A Novel Long Non-Coding RNA, SOX21-AS1, Indicates a Poor Prognosis and Promotes Lung Adenocarcinoma Proliferation

Huang

et al. 2017

Cell Physiol Biochem

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Background:In recent years, long non-coding RNAs (lncRNAs) have been shown to be a novel class of regulators of cancer biological processes. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profiles and potential functions of lncRNAs in lung adenocarcinoma (LUAD). This study evaluated the expression and biological roles of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) in LUAD. Methods: Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression levels of SOX21-AS1 in 68 pairs of LUAD tissues and corresponding non-tumor tissues. The effect of SOX21-AS1 on proliferation was evaluated by MTT, colony formation, EdU assays, flow-cytometric analysis and in vivo tumor formation assays. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of p57. Results: Higher expression levels of SOX21-AS1 positively correlated with tumor size and advanced tumor-node-metastasis (TNM) stage. Multivariate analyses indicated that SOX21-AS1 expression could serve as an independent prognostic factor for overall survival of LUAD. Furthermore, knockdown of SOX21-AS1 significantly inhibited LUAD cell proliferation both in vitro and in vivo and induced cell cycle phase arrest and cell apoptosis. Importantly, through qRT-PCR and western blot analysis, we found that inhibition of SOX21-AS1 remarkably induced p57 expression. Conclusions: Collectively, our study demonstrates that SOX21-AS1 is involved in the development and progression of LUAD and that SOX21-AS1 may be a potential diagnostic factor as well as a target for new therapies for patients with LUAD.X. Lu, C. Huang and X. He contributed equally to this work.

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cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

Cited by 171 publications

References 55 publications

Long Intergenic Noncoding RNA 00511 Acts as an Oncogene in Non–small-cell Lung Cancer by Binding to EZH2 and Suppressing p57

Long Intergenic Noncoding RNA 00511 Acts as an Oncogene in Non–small-cell Lung Cancer by Binding to EZH2 and Suppressing p57

Deregulation of CRTCs in Aging and Age-Related Disease Risk

A Novel Long Non-Coding RNA, SOX21-AS1, Indicates a Poor Prognosis and Promotes Lung Adenocarcinoma Proliferation

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