Knockdown of SF3B1 inhibits cell proliferation, invasion and migration triggering apoptosis in breast cancer via aberrant splicing

Zhang, Ling; Zhang, Xiaojuan; Zhang, Haitao; Liu, Feng; Bi, Yanghui; Zhang, Yanyan; Chen, Cheng; Liu, Jing

doi:10.1007/s12282-020-01045-8

Cited by 14 publications

(19 citation statements)

References 27 publications

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“…Changes in the expression of SFs from the SR protein family have been detected in several solid tumor types. For example, causal links have been identified between AS misregulation and breast cancer (Anczukow et al, 2012; Anczukow et al, 2015; Climente‐Gonzalez et al, 2017; Hu et al, 2020; Koedoot et al, 2019; Sebestyen et al, 2016; Xu et al, 2014; Yoshida et al, 2015; Zhang, Zhang, et al, 2020). Moreover, several SFs are upregulated in breast tumors, and are sufficient to promote tumor initiation in breast cancer models (Anczukow et al, 2012; Anczukow et al, 2015; Karni et al, 2007; Park et al, 2019).…”

Section: Splicing and Age‐related Diseasesmentioning

confidence: 99%

Splicing alterations in healthy aging and disease

Angarola

Anczuków

2021

WIREs RNA

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Alternative RNA splicing is a key step in gene expression that allows generation of numerous messenger RNA transcripts encoding proteins of varied functions from the same gene. It is thus a rich source of proteomic and functional diversity. Alterations in alternative RNA splicing are observed both during healthy aging and in a number of human diseases, several of which display premature aging phenotypes or increased incidence with age. Age‐associated splicing alterations include differential splicing of genes associated with hallmarks of aging, as well as changes in the levels of core spliceosomal genes and regulatory splicing factors. Here, we review the current known links between alternative RNA splicing, its regulators, healthy biological aging, and diseases associated with aging or aging‐like phenotypes. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing

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Section: Splicing and Age‐related Diseasesmentioning

confidence: 99%

Splicing alterations in healthy aging and disease

Angarola

Anczuków

2021

WIREs RNA

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“…In endometrial cancer and several other cancers, SF3B1 appears to act as an oncogene, as most of the mutations occur in hotspots 20 . Besides, overexpression of SF3B1 has also been reported to drive tumorigenesis in several cancers, including breast cancer, prostate cancer, and myelodysplastic syndromes [24][25][26] . Moreover, a recent study revealed that knock down of overexpressed SF3B1 expression reduced breast cancer cell proliferation, migration, and invasion 26 .…”

Section: Introductionmentioning

confidence: 99%

“…Besides, overexpression of SF3B1 has also been reported to drive tumorigenesis in several cancers, including breast cancer, prostate cancer, and myelodysplastic syndromes [24][25][26] . Moreover, a recent study revealed that knock down of overexpressed SF3B1 expression reduced breast cancer cell proliferation, migration, and invasion 26 . However, whether SF3B1 overexpression likewise promotes endometrial cancer progression is unknown.…”

Section: Introductionmentioning

confidence: 99%

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation

Popli¹,

Richters

Chadchan³

et al. 2020

Cell Death Dis

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Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer—alternative mRNA splicing—and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore, SF3B1 knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with SF3B1 knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that SF3B1 depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed KSR2 as a potential candidate for SF3B1-mediated functions in endometrial cancer. Specifically, loss of SF3B1 led to decrease in KSR2 expression, owing to reduced maturation of KSR2 pre-mRNA to a mature RNA. Importantly, we found rescuing the KSR2 expression with SF3B1 knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that SF3B1 plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

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“…MAP3K7, PPP2R5A) (Lieu et al, 2020;Liu et al, 2020;Obeng et al, 2016b), confirming the proto-oncogenic role of SF3B1. Interestingly, recent studies have also found a link between wildtype SF3B1 expression levels and tumor aggressiveness in pancreatic-, endometrial-, prostate-, liver-and breast cancer, with higher expression being associated with adverse prognosis (Alors-Perez et al, 2021;Jiménez-Vacas et al, 2019;López-Cánovas et al, 2021;Popli et al, 2020;Zhang et al, 2020). Considering that in the heart SF3B1 overexpression is induced by hypoxia (Mirtschink et al, 2015), and that solid cancers are often poorly oxygenated (Semenza, 2003), we hypothesized that upregulation of wildtype SF3B1 in tumors facilitates adaptation to hypoxia.…”

Section: Introductionmentioning

confidence: 94%

“…MAP3K7, PPP2R5A) [8][9][10] , confirming the proto-oncogenic role of SF3B1. Interestingly, recent tumor biomarker studies have also found a link between wildtype SF3B1 expression levels and tumor aggressiveness in endometrial-, prostate-, liver-and breast cancer, with higher expression being associated with adverse prognosis [11][12][13][14] . Considering that in heart tissue SF3B1 overexpression is induced by hypoxia 15 , and that solid cancers are often poorly oxygenated 16 , we hypothesized that upregulation of wildtype SF3B1 in tumors facilitates adaptation to hypoxia.…”

Section: Mainmentioning

confidence: 99%

SF3B1 promotes tumor malignancy through splicing-independent activation of HIF1α

Simmler

Cortijo

Koch

et al. 2020

Preprint

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Heterozygous mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies moreover demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, although the underlying mechanisms for this phenomenon remain elusive. Here, we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF)1α through a splicing-independent mechanism. By directly interacting with HIF1α, SF3B1 augments HIF1α-HIF1β heterodimer binding to hypoxia response elements, and facilitates full transcriptional response of HIF target genes. We further validate the relevance of this mechanism for tumor progression, and show that monoallelic deletion of Sf3b1 impedes pancreatic cancer formation via HIF signaling. Altogether our work demonstrates a pivotal role of SF3B1 in the adaptation to hypoxia, suggesting a causal link between high SF3B1 levels and cancer aggressiveness.

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Knockdown of SF3B1 inhibits cell proliferation, invasion and migration triggering apoptosis in breast cancer via aberrant splicing

Cited by 14 publications

References 27 publications

Splicing alterations in healthy aging and disease

Splicing alterations in healthy aging and disease

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation

SF3B1 promotes tumor malignancy through splicing-independent activation of HIF1α

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