An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype

Shapiro, Irina M.; Cheng, Albert W.; Flytzanis, Nicholas C.; Balsamo, Michele; Condeelis, John S.; Oktay, Maja H.; Burge, Christopher B.; Gertler, Frank B.

doi:10.1371/journal.pgen.1002218

Cited by 425 publications

(537 citation statements)

References 69 publications

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“…This suggests that other genes that are directly regulated by GRHL2 indirectly affect processes such as junction assembly and cell polarity at the posttranscriptional or posttranslational level. Potential mechanisms include alternative splicing of transcripts by ESRP1/2 [epithelial splicing regulatory proteins (29)], trafficking of membrane components through RABs, and dynamic interaction of membrane proteins with the cytoskeleton mediated by multiple ARHGEF and ARHGAP family members. Defining the precise hierarchy of mechanisms by which GRHL2 affects epithelial behavior and how these intersect with other regulatory networks will require multiple lines of investigation.…”

Section: Discussionmentioning

confidence: 99%

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Most of the airways of the human lung are lined by an epithelium made up of ciliated and secretory luminal cells and undifferentiated basal progenitor cells. The integrity of this epithelium and its ability to act as a selective barrier are critical for normal lung function. In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air–liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air–liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.

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Section: Discussionmentioning

confidence: 99%

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…One normal function of Muscleblind is to modulate splicing during muscle and heart development [29][30][31][32][33][34] . The second most correlated knockdown was RBFOX2, which is a well-characterized splicing factor that we and others have implicated in epithelial-tomesenchymal transition and invasion 22,23,34,35 . To confirm the association of these two proteins with stem cell differentiation, we knocked down MBNL1 and RBFOX2 in fibroblasts, alone or in combination, and performed automated RT-PCR for the 303 original alternative splicing events.…”

Section: Resultsmentioning

confidence: 95%

MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation

et al. 2013

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Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has provided huge insight into the pathways, mechanisms and transcription factors that control differentiation. Here we use high-throughput RT-PCR technology to take a snapshot of splicing changes in the full spectrum of high-and low-expressed genes during induction of fibroblasts, from several donors, into iPSCs and their subsequent redifferentiation. We uncover a programme of concerted alternative splicing changes involved in late mesoderm differentiation and controlled by key splicing regulators MBNL1 and RBFOX2. These critical splicing adjustments arise early in vertebrate evolution and remain fixed in at least 10 genes (including PLOD2, CLSTN1, ATP2A1, PALM, ITGA6, KIF13A, FMNL3, PPIP5K1, MARK2 and FNIP1), implying that vertebrates require alternative splicing to fully implement the instructions of transcriptional control networks.

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“…It is involved in polyadenylation of the pre-mRNA 3 0 end (31-33) and also plays an important role in translational regulation of a subset of RNA transcription through internal ribosome entry sites (21,(34)(35)(36)(37). As for malignancies, PTBP1 is overexpressed in glioblastoma (7,8) and breast cancer (38), suppresses p27 expression, and contributes largely to cell proliferation (21,39). In zebrafish, PTBP1 ablation leads to increased proliferation and cell apoptosis (40).…”

Section: Discussionmentioning

confidence: 99%

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

Takahashi

Nishimura

Kagawa

et al. 2015

Molecular Cancer Therapeutics

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Polypyrimidine tract-binding protein (PTBP1) is an RNAbinding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2: PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expression levels were positively correlated to poor prognosis and lymph node metastasis. In analyses of colorectal cancer cells using siRNA for PTBP1, we observed that PTBP1 affects cell invasion, which was partially correlated to CD44 splicing, and this correlation was also confirmed in clinical samples. PTBP1 expression also affected anchorage-independent growth in colorectal cancer cell lines. PTBP1 expression also affected cell proliferation. Using timelapse imaging analysis, PTBP1 was implicated in prolonged G 2 -M phase in HCT116 cells. As for the mechanism of prolonged G 2 -M phase in HCT116 siPTBP1 cells, Western blotting revealed that PTBP1 expression level was correlated to CDK11 p58 expression level, which was reported to play an important role on progression to complete mitosis. These findings indicated that PTBP1 is a potential therapeutic target for colorectal cancer.

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An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype

Cited by 425 publications

References 69 publications

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

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