Alternative splicing of BCL‑X and implications for treating hematological malignancies (Review)

Chen, Wan-Ling; Li, Jinggang

doi:10.3892/ol.2021.12931

Cited by 4 publications

(3 citation statements)

References 78 publications

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“…Studies to date have shown that the BCL-x gene, a member of the BCL-2 family, enables different transcripts from the same gene to have the same or different expression patterns and functions through alternative splicing. 16 Therefore, we selected all transcripts and the transcript NR 134251.1 of APTR in this study to research its function and mechanism. 16HBE cells were treated with different concentrations of sodium arsenite for 48 h, and the expression of all transcripts and the transcript NR 134251.1 of lncRNA APTR showed a dose-dependent promotion.…”

Section: Discussionmentioning

confidence: 99%

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes

Shen

et al. 2023

Hum Exp Toxicol

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Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure.

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Section: Discussionmentioning

confidence: 99%

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes

Shen

et al. 2023

Hum Exp Toxicol

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“…For example, the alternative isoform of CD44, which is extensively studied across various cancer types, is linked to the epithelial-to-mesenchymal transition ( 31 ). The utilization of alternative 5′ splice sites in Bcl-x pre-mRNA results in the formation of the anti-apoptotic Bcl-x(L) and pro-apoptotic Bcl-x(S) protein isoforms ( 32 , 33 ). Bcl-x(L) is transcriptionally upregulated in numerous cancers and is linked to chemoresistance, as well as to the RAS-induced expression of stemness regulators and the preservation of a cancer-initiating cell phenotype ( 34 ).…”

Section: Concise View Of the Alternative Splicing In Cancermentioning

confidence: 99%

Neoantigens in cancer immunotherapy: focusing on alternative splicing

Huang,

Wen,

Tuerhong

et al. 2024

Front. Immunol.

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Alternative splicing (AS) functions as a crucial program in transcriptional modulation, leading to proteomic diversity and functional alterations of proteins. These splicing actions induce various neoantigens that hold prognostic significance and contribute to various aspects of cancer progression, including immune responses against cancer. The advent of immunotherapy has remarkably revolutionized tumor therapy. In this regard, AS-derived neoantigens are potent targets for cancer vaccines and chimeric antigen receptor (CAR) T cell therapies. In this review, we outline that AS-derived neoantigens serve as promising immunotherapeutic targets and guide immunotherapy strategies. This evidence contributes to a deeper comprehension of the complexity of proteomic diversity and provides novel perspectives and techniques for precision medicine in immunotherapy. Moreover, we underscore the obstacles that are awaited to be addressed for this novel approach to become clinically applicable.

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“…Hence, depending on the balance between Bcl-xL and Bcl-xS, BCL-x can either be pro- or anti-apoptotic. As such, the balance between these two antagonistic isoforms is tightly regulated and overexpression of the anti-apoptotic Bcl-xL isoform has been linked to resistance to chemotherapy in several cancers ( 12 , 13 ), whereas overexpression of the pro-apoptotic Bcl-xS isoform is associated to some forms of diabetes and cardiac disorders ( 14 , 15 ). Therefore, pharmacological means to switch the splicing in favour of Bcl-xS may have therapeutic benefits for a number of cancers, in particular those resistant to chemotherapy due to Bcl-xL overexpression.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing of BCL-x is controlled by RBM25 binding to a G-quadruplex in BCL-x pre-mRNA

Le Sénéchal,

Keruzoré,

Quillévéré

et al. 2023

Nucleic Acids Research

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BCL-x is a master regulator of apoptosis whose pre-mRNA is alternatively spliced into either a long (canonical) anti-apoptotic Bcl-xL isoform, or a short (alternative) pro-apoptotic Bcl-xS isoform. The balance between these two antagonistic isoforms is tightly regulated and overexpression of Bcl-xL has been linked to resistance to chemotherapy in several cancers, whereas overexpression of Bcl-xS is associated to some forms of diabetes and cardiac disorders. The splicing factor RBM25 controls alternative splicing of BCL-x: its overexpression favours the production of Bcl-xS, whereas its downregulation has the opposite effect. Here we show that RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA that forms at the vicinity of the alternative 5′ splice site leading to the alternative Bcl-xS isoform. This RBM25/rG4 interaction is crucial for the production of Bcl-xS and depends on the RE (arginine-glutamate-rich) motif of RBM25, thus defining a new type of rG4-interacting domain. PhenDC3, a benchmark G4 ligand, enhances the binding of RBM25 to the GQ-2 rG4 of BCL-x pre-mRNA, thereby promoting the alternative pro-apoptotic Bcl-xS isoform and triggering apoptosis. Furthermore, the screening of a combinatorial library of 90 putative G4 ligands led to the identification of two original compounds, PhenDH8 and PhenDH9, superior to PhenDC3 in promoting the Bcl-xS isoform and apoptosis. Thus, favouring the interaction between RBM25 and the GQ-2 rG4 of BCL-x pre-mRNA represents a relevant intervention point to re-sensitize cancer cells to chemotherapy.

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Alternative splicing of BCL‑X and implications for treating hematological malignancies (Review)

Cited by 4 publications

References 78 publications

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes

Neoantigens in cancer immunotherapy: focusing on alternative splicing

Alternative splicing of BCL-x is controlled by RBM25 binding to a G-quadruplex in BCL-x pre-mRNA

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