Insights into Telomerase/hTERT Alternative Splicing Regulation Using Bioinformatics and Network Analysis in Cancer

The reactivation of telomerase in cancer cells remains incompletely understood. The catalytic component of telomerase, hTERT, is thought to be the limiting component in cancer cells for the formation of active enzymes. hTERT gene expression is regulated at several levels including chromatin, DNA methylation, transcription factors, and RNA processing events. Of these regulatory events, RNA processing has received little attention until recently. RNA processing and alternative splicing regulation have been explored to understand how hTERT is regulated in cancer cells. The cis- and trans-acting factors that regulate the alternative splicing choice of hTERT in the reverse transcriptase domain have been investigated. Further, it was discovered that the splicing factors that promote the production of full-length hTERT were also involved in cancer cell growth and survival. The goals are to review telomerase regulation via alternative splicing and the function of hTERT splicing variants and to point out how bioinformatics approaches are leading the way in elucidating the networks that regulate hTERT splicing choice and ultimately cancer growth.

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Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

International Journal of Molecular Sciences ◽

10.3390/ijms21145161 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5161 ◽

Cited By ~ 1

Author(s):

Katarzyna Taylor ◽

Krzysztof Sobczak

Keyword(s):

Alternative Splicing ◽

Rna Structure ◽

The Other ◽

Splicing Regulation ◽

Rna Structures ◽

Structural Arrangement ◽

Biological Functionality ◽

Cis And Trans ◽

Structural Aspects

Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields.

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Abstract 2083: Alternative splicing regulation by the androgen receptor in prostate cancer cells

10.1158/1538-7445.am2020-2083 ◽

2020 ◽

Author(s):

Lucas Germain ◽

Camille Lafront ◽

Jolyane Beaudette ◽

Raghavendra Tejo Karthik Poluri ◽

Cindy Weidmann ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Alternative Splicing ◽

Cancer Cells ◽

Splicing Regulation ◽

Prostate Cancer Cells

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Impact of Alternative Splicing Variants on Liver Cancer Biology

Cancers ◽

10.3390/cancers14010018 ◽

2021 ◽

Vol 14 (1) ◽

pp. 18

Author(s):

Jose J. G. Marin ◽

Maria Reviejo ◽

Meraris Soto ◽

Elisa Lozano ◽

Maitane Asensio ◽

...

Keyword(s):

Alternative Splicing ◽

Cancer Cells ◽

Cancer Biology ◽

Survival Rates ◽

Splicing Factors ◽

Aberrant Splicing ◽

Splicing Variants ◽

Mrna Maturation ◽

Available Information ◽

The Impact

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

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Cancer Cell Growth in the Near Infrared Region by Using Silica Coated Gold Nanorods

NANO ◽

10.1142/s1793292020500010 ◽

2020 ◽

Vol 15 (01) ◽

pp. 2050001 ◽

Cited By ~ 1

Author(s):

Tuntun Wang ◽

Kwi Seok Yeom ◽

Sitansu Sekhar Nanda ◽

Seong Soo A. An ◽

Dong Kee Yi

Keyword(s):

Protein Folding ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Gold Nanorods ◽

Near Infrared ◽

Infrared Region ◽

Cancer Cell Growth ◽

Growth And Survival ◽

Cell Behaviors

Gold nanorods (AuNRs) have been considered as suitable materials for diverse biomedical applications in controlling cell behaviors. The nanoisland system with well-dispersed silica coated Au nanorods (Si-AuNRs) was used to demonstrate the enhanced cell growth of normal and cancer cells (MDA-MB-231 mammalian breast cancer cells) from the induced expressions of the heat shock proteins (HSPs). The over-expressions of HSP could help in protein folding in cell proliferations and growths of both the normal and cancer cells. In the current study, interesting mechanisms of cancer cell growth with Si-AuNRs than the conventional systems, such as incubator, would be presented. We believe that the growth of cancer cells in near infrared (NIR) region using Si-AuNRs induced the activities of HSPs, which could help the protein folding in cell growth and survival in comparison to the cells grown in the incubator only. The cell growth enhancing technology could be expanded in diverse applications in cell culture systems.

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Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster?

Cancers ◽

10.3390/cancers11060804 ◽

2019 ◽

Vol 11 (6) ◽

pp. 804 ◽

Cited By ~ 15

Author(s):

Jie Jiang ◽

Sankalp Srivastava ◽

Ji Zhang

Keyword(s):

Amino Acid ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Therapeutic Strategy ◽

Glutamine Metabolism ◽

Cancer Cell Growth ◽

Growth And Survival ◽

Tumor Environment ◽

Cell Growth And Survival

Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for cancer cell growth and survival. It is well-accepted that glutamine is a versatile biosynthetic substrate in cancer cells beyond its role as a proteinogenic amino acid. In addition, accumulating evidence suggests that glutamine metabolism is regulated by many factors, including tumor origin, oncogene/tumor suppressor status, epigenetic alternations and tumor microenvironment. However, despite the emerging understanding of why cancer cells depend on glutamine for growth and survival, the contribution of glutamine metabolism to tumor progression under physiological conditions is still under investigation, partially because the level of glutamine in the tumor environment is often found low. Since targeting glutamine acquisition and utilization has been proposed to be a new therapeutic strategy in cancer, it is central to understand how tumor cells respond and adapt to glutamine starvation for optimized therapeutic intervention. In this review, we first summarize the diverse usage of glutamine to support cancer cell growth and survival, and then focus our discussion on the influence of other nutrients on cancer cell adaptation to glutamine starvation as well as its implication in cancer therapy.

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Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

Genes ◽

10.3390/genes12071085 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1085

Author(s):

Nikolay Mehterov ◽

Maria Kazakova ◽

Yordan Sbirkov ◽

Boyan Vladimirov ◽

Nikolay Belev ◽

...

Keyword(s):

Alternative Splicing ◽

Cancer Cells ◽

Tumor Cells ◽

Rna Splicing ◽

Molecular Mechanisms ◽

Chemotherapeutic Agents ◽

Human Genes ◽

Splicing Variants ◽

Almost All ◽

Aberrant Rna

Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.

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Alternative splicing regulation by the androgen receptor in prostate cancer cells

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2020.105710 ◽

2020 ◽

Vol 202 ◽

pp. 105710 ◽

Cited By ~ 1

Author(s):

Lucas Germain ◽

Camille Lafront ◽

Jolyane Beaudette ◽

Raghavendra Tejo Karthik Poluri ◽

Cindy Weidmann ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Alternative Splicing ◽

Cancer Cells ◽

Splicing Regulation ◽

Prostate Cancer Cells

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The Scaffold Protein IQGAP1 Links Heat-Induced Stress Signals to Alternative Splicing Regulation in Gastric Cancer Cells

SSRN Electronic Journal ◽

10.2139/ssrn.3724977 ◽

2020 ◽

Author(s):

Andrada Birladeanu ◽

Malgorzata Rogalska ◽

Myrto Potiri ◽

Vasiliki Papadaki ◽

Margarita Andreadou ◽

...

Keyword(s):

Gastric Cancer ◽

Alternative Splicing ◽

Cancer Cells ◽

Scaffold Protein ◽

Splicing Regulation ◽

Gastric Cancer Cells ◽

Induced Stress ◽

Stress Signals

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The Role of Translation Control in Tumorigenesis and Its Therapeutic Implications

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030419-033420 ◽

2020 ◽

Vol 4 (1) ◽

pp. 437-457

Author(s):

Yichen Xu ◽

Davide Ruggero

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Mrna Translation ◽

Translation Control ◽

Cancer Cell Growth ◽

Growth And Survival ◽

Therapeutic Implications ◽

Key Driver ◽

Oncogenic Stress

As a convergent mechanism downstream of most oncogenic signals, control of mRNA translation has emerged as a key driver in establishing and tuning gene expression at specific steps in cancer development. Translation control is the most energetically expensive molecular process in the cell that needs to be modulated upon adaption to limited cellular resources, such as cellular stress. It thereby serves as the Achilles’ heel for cancer cells, particularly in response to changes in the microenvironment as well as to nutrient and metabolic shifts characteristic of cancer cell growth and metastasis. In this review, we discuss emerging discoveries that reveal how cancer cells modulate the translation machinery to adapt to oncogenic stress, the mechanisms that guide mRNA translation specificity in cancer, and how this selective mode of gene regulation provides advantages for cancer progression. We also provide an overview of promising preclinical and clinical efforts aimed at targeting the unique vulnerabilities of cancer cells that rely on the remodeling of mRNA translation for their infinite growth and survival.

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Alternative Splicing Variants of IκBβ Establish Differential NF-κB Signal Responsiveness in Human Cells

Molecular and Cellular Biology ◽

10.1128/mcb.18.5.2596 ◽

1998 ◽

Vol 18 (5) ◽

pp. 2596-2607 ◽

Cited By ~ 37

Author(s):

Fuminori Hirano ◽

Mirra Chung ◽

Hirotoshi Tanaka ◽

Naoki Maruyama ◽

Isao Makino ◽

...

Keyword(s):

Alternative Splicing ◽

Rna Processing ◽

Abundant Species ◽

Human Cells ◽

Protein Isoforms ◽

Activation Mechanism ◽

Proteolytic Degradation ◽

Phosphorylation Sites ◽

Splicing Variants ◽

Carboxy Terminal

ABSTRACT To release transcription factor NF-κB into the nucleus, the mammalian IκB molecules IκBα and IκBβ are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-κB/Rel family, the different IκB molecules could vary in their specific NF-κB/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-κB function by IκBβ relative to IκBα. Via alternative RNA processing, human IκBβ gives rise to different protein isoforms. IκBβ1 and IκBβ2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. IκBβ2 is the most abundant species in a number of human cell lines tested, whereas IκBβ1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-κB/Rel homo- and heterodimers, which are distinct from those of IκBα, and both are constitutively phosphorylated. In unstimulated B cells, however, IκBβ1, but not IκBβ2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While IκBβ1 is nearly as responsive as IκBα, indicative of a shared activation mechanism, IκBβ2 is only weakly degraded and often not responsive at all. Alternative splicing of the IκBβ pre-mRNA may thus provide a means to selectively control the amount of IκBβ-bound NF-κB heteromers to be released under NF-κB stimulating conditions.

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