Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction.

Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid 11-ß dehydrogenase 1 like gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment.

New Histamine-Related Five-Membered N-Heterocycle Derivatives as Carbonic Anhydrase I Activators.

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.

Cannabidiol Inhibits Tau Aggregation In Vitro.

A hallmark of Alzheimer's disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), and atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking, and job's plot, we further demonstrated that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking, and Thioflavin T assay further established that the main forces are hydrogen Van der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.

Alternative RNA Splicing-The Trojan Horse of Cancer Cells in Chemotherapy.

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.

Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect.

Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.

Skin aquaporins as druggable targets: Promoting health by addressing the disease.

Skin is the most vulnerable organ of the human body since it is the first line of defense, covering the entire external body surface. Additionally, skin has a critical role in thermoregulation, sensation, immunological surveillance, and biochemical processes such as Vitamin D3 production by ultraviolet irradiation. The ability of the skin layers and resident cells to maintain skin physiology, such as hydration, regulation of keratinocytes proliferation and differentiation and wound healing, is supported by key proteins such as aquaporins (AQPs) that facilitate the movements of water and small neutral solutes across membranes. Various AQP isoforms have been detected in different skin-resident cells where they perform specific roles, and their dysregulation has been associated with several skin pathologies. This review summarizes the current knowledge of AQPs involvement in skin physiology and pathology, highlighting their potential as druggable targets for the treatment of skin disorders.

Dopamine-induced interactions of female mouse hypothalamic proteins with progestin receptor-A in the absence of hormone.

Neural progestin receptors (PR) function in reproduction, neural development, neuroprotection, learning, memory and the anxiety response. In the absence of progestins, PR can be activated by dopamine (DA) in the rodent hypothalamus to elicit female sexual behaviour. The present study investigated mechanisms of DA activation of PR by testing the hypothesis that proteins from DA-treated hypothalami interact with PR in the absence of progestins. Ovariectomised, oestradiol-primed mice were infused with a D1-receptor agonist, SKF38393 (SKF), into the third ventricle 30 minutes prior to death. Proteins from SKF-treated hypothalami were pulled-down with glutathione S-transferase-tagged mouse PR-A or PR-B and the interactomes were analysed by mass spectrometry. The largest functional group to interact with PR-A in a DA-dependent manner was synaptic proteins. To test the hypothesis that DA activation of PR regulates synaptic proteins, we developed oestradiol-induced PR-expressing hypothalamic-like neurones derived from human-induced pluripotent stem cells (hiPSCs). Similar to progesterone (P4), SKF treatment of hiPSCs increased synapsin1/2 expression. This SKF-dependent effect was blocked by the PR antagonist RU486, suggesting that PR are necessary for this DA-induced increase. The second largest DA-dependent PR-A protein interactome comprised metabolic regulators involved in glucose metabolism, lipid synthesis and mitochondrial energy production. Interestingly, hypothalamic proteins interacted with PR-A, but not PR-B, in an SKF-dependent manner, suggesting that DA promotes the interaction of multiple hypothalamic proteins with PR-A. These in vivo and in vitro results indicate novel mechanisms by which DA can differentially activate PR isoforms in the absence of P4 and provide a better understanding of ligand-independent PR activation in reproductive, metabolic and mental health disorders in women.

Differential sensitivity of acute myeloid leukemia cells to daunorubicin depends on P2X7A versus P2X7B receptor expression.

Acute myeloid leukemia (AML) is a common adult leukemia often arising from a preexistent myelodysplastic syndrome (MDS). High mortality rates of AML are caused by relapse and chemoresistance; therefore, we analyzed the role of P2X7 receptor (P2X7R) splice variants A and B in AML progression and response to chemotherapy. The expression of P2X7RA and P2X7RB was investigated in samples obtained from MDS and AML untreated subjects or AML patients in relapse or remission after chemotherapy. Both P2X7RA and P2X7RB were overexpressed in AML versus MDS suggesting a disease-promoting function. However, in relapsing patients, P2X7RA was downmodulated, while P2X7RB was upmodulated. Treatment with daunorubicin (DNR), one of the main chemotherapeutics for AML, upregulated P2X7RB expression while reducing P2X7RA mRNA in AML blasts. Interestingly, DNR administration also caused ATP release from AML blasts suggesting that, following chemotherapy, activation of the receptor isoforms via their agonist will be responsible for the differential survival of blasts overexpressing P2X7RA versus P2X7RB. Indeed, AML blasts expressing high levels of P2X7RA were more prone to cell death if exposed to DNR, while those overexpressing P2X7RB were more vital and even protected against DNR toxicity. These data were reproducible also in HEK-293 cells separately expressing P2X7RA and B. P2X7RA facilitation of DNR toxicity was in part due to increased uptake of the drug inside the cell that was lost upon P2X7RB expression. Finally, in an AML xenograft model administration of DNR or the P2X7R antagonist, AZ10606120 significantly reduced leukemic growth and coadministration of the drugs proved more efficacious than single treatment as it reduced both P2X7RA and P2X7RB levels and downmodulated c-myc oncogene. Taken together, our data suggest P2X7RA and P2X7RB as potential prognostic markers for AML and P2X7RB as a therapeutic target to overcome chemoresistance in AML relapsing patients.

Calcineurin inhibitor (CNI)-associated skin cancers: New insights on exploring mechanisms by which CNIs downregulate DNA repair machinery.

The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAß). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.

Selective Activation of ZAK ß Expression by 3-Hydroxy-2-Phenylchromone Inhibits Human Osteosarcoma Cells and Triggers Apoptosis via JNK Activation.

Although various advancements in radical surgery and neoadjuvant chemotherapy have been developed in treating osteosarcoma (OS), their clinical prognosis remains poor. A synthetic chemical compound, 3-hydroxylflavone, that is reported to regulate ROS production is known to inhibit human bone osteosarcoma cells. However, its role and mechanism in human OS cells remains unclear. In this study, we have determined the potential of 3-Hydroxy-2-phenylchromone (3-HF) against OS using human osteosarcoma (HOS) cells. Our previous studies showed that Zipper sterile-alpha-motif kinase (ZAK), a kinase member of the MAP3K family, was involved in various cellular events such as cell proliferation and cell apoptosis, and encoded two transcriptional variants, ZAKα and ß. In this study, we show that 3-HF induces the expression of ZAK and thereby enhances cellular apoptosis. Using gain of function and loss of function studies, we have demonstrated that ZAK activation by 3-HF in OS cells is confined to a ZAKß form that presumably plays a leading role in triggering ZAKα expression, resulting in an aggravated cancer apoptosis. Our results also validate ZAKß as the predominant form of ZAK to drive the anticancer mechanism in HOS cells.

Antimycin A increases bronchopulmonary C-fiber excitability via protein kinase C alpha.

Inflammation can increase the excitability of bronchopulmonary C-fibers leading to excessive sensations and reflexes (e.g. wheeze and cough). We have previously shown modulation of peripheral nerve terminal mitochondria by antimycin A causes hyperexcitability in TRPV1-expressing bronchopulmonary C-fibers through the activation of protein kinase C (PKC). Here, we have investigated the PKC isoform responsible for this signaling. We found PKCß1, PKCδ and PKCε were expressed by many vagal neurons, with PKCα and PKCß2 expressed by subsets of vagal neurons. In dissociated vagal neurons, antimycin A caused translocation of PKCα but not the other isoforms, and only in TRPV1-lineage neurons. In bronchopulmonary C-fiber recordings, antimycin A increased the number of action potentials evoked by α,ß-methylene ATP. Selective inhibition of PKCα, PKCß1 and PKCß2 with 50 nM bisindolylmaleimide I prevented the antimycin-induced bronchopulmonary C-fiber hyperexcitability, whereas selective inhibition of only PKCß1 and PKCß2 with 50 nM LY333531 had no effect. We therefore conclude that PKCα is required for antimycin-induced increases in bronchopulmonary C-fiber excitability.

Comparison of the ligand-binding properties of fluorescent VEGF-A isoforms to VEGF receptor 2 in living cells and membrane preparations using NanoBRET.

BACKGROUND AND PURPOSE: Vascular endothelial growth factor A (VEGF-A) is a key mediator of angiogenesis. A striking feature of the binding of a fluorescent analogue of VEGF165 a to nanoluciferase-tagged VEGF receptor 2 (VEGFR2) in living cells is that the BRET signal is not sustained and declines over time. This may be secondary to receptor internalisation. Here, we have compared the binding of three fluorescent VEGF-A isoforms to VEGFR2 in cells and isolated membrane preparations. EXPERIMENTAL APPROACH: Ligand-binding kinetics were monitored in both intact HEK293T cells and membranes (expressing nanoluciferase-tagged VEGFR2) using BRET between tagged receptor and fluorescent analogues of VEGF165 a, VEGF165 b, and VEGF121 a. VEGFR2 endocytosis in intact cells expressing VEGFR2 was monitored by following the appearance of fluorescent ligand-associated receptors in intracellular endosomes using automated quantitative imaging. KEY RESULTS: Quantitative analysis of the effect of fluorescent VEGF-A isoforms on VEGFR2 endocytosis in cells demonstrated that they produce a rapid and potent translocation of ligand-bound VEGFR2 into intracellular endosomes. NanoBRET can be used to monitor the kinetics of the binding of fluorescent VEGF-A isoforms to VEGFR2. In isolated membrane preparations, ligand-binding association curves were maintained for the duration of the 90-min experiment. Measurement of the koff at pH 6.0 in membrane preparations indicated shorter ligand residence times than those obtained at pH 7.4. CONCLUSIONS AND IMPLICATIONS: These studies suggest that rapid VEGF-A isoform-induced receptor endocytosis shortens agonist residence times on the receptor (1/koff ) as VEGFR2 moves from the plasma membrane to the intracellular endosomes.

Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels.

Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27.67 (15.68-39.66) µmol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Nav1.7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more than 10 min to achieve steady-state inhibition when LA (300 µmol/L) was administered. Unlike tetracaine and bupivacaine, LA affected neither the voltage-dependent activation nor the inactivation of the channels. Five residues in domain III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics. These results may help to understand the featured analgesic activity of LA, thus benefiting its application in the clinic and future drug development.

Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs.

BACKGROUND: The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. RESULTS: Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. CONCLUSIONS: In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.

Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts.

Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAα and ß isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAα knockout (CnAα-/-) and CnAß knockout (CnAß-/-) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAα-/- cells and lowest in CnAß-/- cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAα-/- nor CnAß-/- renal fibroblasts. These results indicate that MMP-9 secretion is CnA-isoform specific, i.e. the CnAß isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAα does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated.

Expeditious synthesis of polyacetylenic water hemlock toxins and their effects on the major GABAA receptor isoform.

Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives.

Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets.

A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.

Direct modification of the 5-HT3 receptor current by some anticancer drugs.

The serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor is an important target in the control of emesis, and 5-HT3 receptor antagonists are effective against the early phase chemotherapy evoked vomiting. We recently reported that the anticancer drugs irinotecan and topotecan directly modulate the 5-HT-mediated 5-HT3 receptor current in vitro. In addition, the drug response depends on the 5-HT3 subunit composition. Here, we explored the effects of 35 anticancer drugs on the 5-HT3 receptor current. We microinjected Xenopus laevis oocytes with human 5-HT3A cRNA or a combination of human 5-HT3A and human 5-HT3B cRNA, and performed two-electrode voltage clamp recordings of 5-HT3A and 5-HT3AB receptor currents in the presence of each of the 35 drugs. Over 25% of the drugs we tested inhibited or potentiated the 5-HT3 receptor current. The drugs that modulated the 5-HT3 receptor current had molecular weights of approximately 500. These results implied that these anticancer drugs could affect 5-HT3 receptor.

To4, the first Tityus obscurus ß-toxin fully electrophysiologically characterized on human sodium channel isoforms.

Many scorpion toxins that act on sodium channels (NaScTxs) have been characterized till date. These toxins may act modulating the inactivation or the activation of sodium channels and are named α- or ß-types, respectively. Some venom toxins from Tityus obscurus (Buthidae), a scorpion widely distributed in the Brazilian Amazon, have been partially characterized in previous studies; however, little information about their electrophysiological role on sodium ion channels has been published. In the present study, we describe the purification, identification and electrophysiological characterization of a NaScTx, which was first described as Tc54 and further fully sequenced and renamed To4. This toxin shows a marked ß-type effect on different sodium channel subtypes (hNav1.1-hNav1.7) at low concentrations, and has more pronounced activity on hNav1.1, hNav1.2 and hNav1.4. By comparing To4 primary structure with other Tityus ß-toxins which have already been electrophysiologically tested, it is possible to establish some key amino acid residues for the sodium channel activity. Thus, To4 is the first toxin from T. obscurus fully electrophysiologically characterized on different human sodium channel isoforms.

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform.

Alternative pre-mRNA splicing is a crucial process that allows the generation of diversified RNA and protein products from a multi-exon gene. In tumor cells, this mechanism can facilitate cancer development and progression through both creating oncogenic isoforms and reducing the expression of normal or controllable protein species. We recently demonstrated that an alternative cyclin D-binding myb-like transcription factor 1 (DMTF1) pre-mRNA splicing isoform, DMTF1ß, is increasingly expressed in breast cancer and promotes mammary tumorigenesis in a transgenic mouse model. Aberrant pre-mRNA splicing is a typical event occurring for many cancer-related functional proteins. In this review, we introduce general aberrant pre-mRNA splicing in cancers and discuss its therapeutic application using our recent discovery of the oncogenic DMTF1 isoform as an example. We also summarize new insights in designing novel targeting strategies of cancer therapies based on the understanding of deregulated pre-mRNA splicing mechanisms.