Hallmarks of cancer and <scp>AU</scp>‐rich elements

Khabar, Khalid S.A.

doi:10.1002/wrna.1368

Cited by 68 publications

(65 citation statements)

References 208 publications

(307 reference statements)

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“…The mRNAs with AU-rich elements (AREs) in their 3′-UTR constitute ∼10–15% of all the transcripts that span genes related to inflammation, transcription, cell proliferation, RNA metabolism, development, and cellular signaling, which play important roles in tumorigenesis (4–6). However, the role of ARE-BPs in lung cancer remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer

Bikkavilli¹,

Zerayesus²,

Scoyk³

et al. 2017

Journal of Biological Chemistry

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AU-rich element-binding proteins (ARE-BPs) offer post-transcriptional regulation of gene expression via physical interaction and recruitment of RNA decay machinery to the AU-rich elements within the 3′-UTR of the target transcripts. However, the role of ARE-BPs in lung cancer remains poorly understood. In this study, we have identified that K-homology splicing regulatory protein (KSRP), an ARE-BP, is robustly up-regulated in human lung cancer. Importantly, Kaplan-Meier survival analysis indicated that elevated KSRP expression was correlated with poor overall survival of lung cancer patients. Furthermore, cigarette smoke, a leading risk factor for lung cancer, was also identified to be an important contributor to increased KSRP expression. Remarkably, silencing of KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion, suggesting an oncogenic role for KSRP in lung cancer. Finally, we provide mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism, i.e. post-transcriptional mRNA regulation.

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Section: Introductionmentioning

confidence: 99%

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer

Bikkavilli¹,

Zerayesus²,

Scoyk³

et al. 2017

Journal of Biological Chemistry

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“…A common feature of mRNAs, which are post-transcriptionally regulated by RBPs, is the presence of so-called AU-rich elements (AREs) within the 3′ untranslated regions. Such AREs constitute binding sites for many RBPs, thus providing the platform for versatile post-transcriptional regulation by different RBP interaction patterns 30. In line with the observation that HuR does not affect CCL5 expression posttranscriptionally, the CCL5 mRNA does not contain predictable AREs.…”

mentioning

confidence: 85%

The RNA‐binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors

Brauß

Winslow

Lampe

et al. 2017

Molecular Carcinogenesis

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The RNA-binding protein HuR promotes tumor growth by affecting proliferation, metastasis, apoptosis, and angiogenesis. Although immune cells, especially tumor-associated macrophages, are critical components of the tumor stroma, the influence of HuR in tumors on the recruitment of immune cells remains poorly understood. In the present study, we, therefore, aimed to elucidate the impact of tumor cell HuR on the interaction between tumor cells and macrophages. To this end, we stably depleted HuR in human MCF-7 breast cancer cells. We found that HuR-deficient cells not only showed reduced proliferation, they further expressed elevated levels of the chemokine CCL5. HuR-dependent repression of CCL5 was neither caused by altered CCL5 mRNA stability, nor by changes in CCL5 translation. Instead, loss of HuR augmented transcription of CCL5, which was mediated via an interferon-stimulated response element in the CCL5 promoter. Furthermore, HuR depletion enhanced macrophage recruitment into MCF-7 tumor spheroids, an effect which was completely lost upon neutralization of CCL5. HuR expression further negatively correlated with CCL5 expression and macrophage appearance in a cohort of breast tumors. Thus, while HuR is well-characterized to support various pro-tumorigenic features in tumor cells, we provide evidence that it limits the recruitment of macrophages into tumors by repressing CCL5. As macrophage infiltration is associated with poor prognosis, our findings underline the highly cell-type and context specific role of HuR in tumorigenesis.

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“…HuR is a member of the ELAV family of RBPs (for an extensive review of this family of proteins please see Hinman & Lou ()) and consists of two‐tandem RNA recognition motif (RRM) domains, followed by a hinge region and a third RRM domain (Brennan & Steitz, ; Meisner & Filipowicz, ). HuR binds to adenylate uridylate (AU)‐rich elements (AREs) typically located in the 3′‐untranslated regions (3′UTRs) of specific target genes involved in cell survival and tumorigenesis (Abdelmohsen & Gorospe, ; Blanco, Jimbo, et al, ; Brody & Gonye, ; Costantino et al, ; Khabar, ; Lal et al, ). HuR is predominantly localized to the nucleus (>90%) and can shuttle between the nucleus and the cytoplasm.…”

Section: An Alternative To Driver Genetic Events: a Critical Posttranmentioning

confidence: 99%

Complex HuR function in pancreatic cancer cells

Brody

Dixon

2018

WIREs RNA

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal patient outcomes. The underlying core genetic drivers of disease have been identified in human tumor specimens and described in genetically engineered mouse models. These genetic drivers of PDAC include KRAS signaling, TP53 mutations, and genetic loss of the SMAD4 tumor suppressor protein. Beyond the known mutational landscape of PDAC genomes, alternative disrupted targets that extend beyond conventional genetic mutations have been elusive and understudied in the context of PDAC cell therapeutic resistance and survival. This last point is important because PDAC tumors have a unique and complex tumor microenvironment that includes hypoxic and nutrient-deprived niches that could select for cell populations that garner therapeutic resistance, explaining tumor heterogeneity in regards to response to different therapies. We and others have embarked in a line of investigation focused on the key molecular mechanism of posttranscriptional gene regulation that is altered in PDAC cells and supports this pro-survival phenotype intrinsic to PDAC cells. Specifically, the key regulator of this mechanism is a RNA-binding protein, HuR (ELAVL1), first described in cancer nearly two decades ago. Herein, we will provide a brief overview of the work demonstrating the importance of this RNA-binding protein in PDAC biology and then provide insight into ongoing work developing therapeutic strategies aimed at targeting this molecule in PDAC cells.

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Hallmarks of cancer and AU‐rich elements

Cited by 68 publications

References 208 publications

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer

The RNA‐binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors

Complex HuR function in pancreatic cancer cells

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