Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Xu, Yilin; Gao, Xin D.; Lee, Jae Hyung; Huang, Huilin; Tan, Haidong; Ahn, Jaegyoon; Reinke, Lauren M.; Marynen, Peter; Feng, Yue; Gius, David; Siziopikou, Kalliopi P.; Peng, Junmin; Xiao, Xinshu; Cheng, Chonghui

doi:10.1101/gad.241968.114

Cited by 207 publications

(267 citation statements)

References 65 publications

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“…Recent data indicate that it acts in an opposite way to ESRP1 and is crucial for EMT and metastasis by supporting CD44s splicing. 51 In addition to the antagonistic role of hnRNPM/ESRP1, our data support that EMT-specific splicing is also regulated by qRT-PCR expression analysis of CD44 isoforms at different time-points during a 21-day TGFb treatment of MCF10A cells. Analysis was performed by using specific primers for variants containing sequences encoded by exons v2 to v10.…”

Section: Discussionsupporting

confidence: 63%

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

Preca

Bajdak

Mock

et al. 2015

Intl Journal of Cancer

159

138

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Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.Tumor recurrence and metastasis represent the two major obstacles in the successful treatment of cancer. Increasing evidence suggests that the aggressive phenotype of this disease is associated with the activation of an embryonic program termed epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose apical-basal cell polarity and change to a mesenchymal phenotype. [1][2][3] In order to initiate and complete an EMT, several distinct molecular programsKey words: cancer stem cells, epithelial-mesenchymal transition (EMT), metastasis, drug resistance, differential splicing Abbreviations: bHLH: basic helix-loop-helix; CD44s: cluster of differentiation 44, standard isoform; CD44v: cluster of differentiation 44, variant isoforms; ChIP: chromatin immunoprecipitation; CSC: cancer stem cell; Dox: doxycycline; EGF: epidermal growth factor; EMT: epithelial-mesenchymal transition; ESRP1: epithelial splicing regulatory protein 1; FGF: fibroblast growth factor; HGF/SF: hepatic growth factor/scatter factor; hnRNPM: heterogeneous nuclear ribonucleoprotein M; PDAC: pancreas ductal adenocarcinoma; shRNA: small hairpin ribonucleic acid; siRNA: small interference ribonucleic acid; TGFb: transforming growth factor b; ZEB: zinc-finger and E-box binding; ZFH: zinc-finger homeodomain

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Section: Discussionsupporting

confidence: 63%

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

Preca

Bajdak

Mock

et al. 2015

Intl Journal of Cancer

159

138

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“…[26][27][28] Several studies have shown the involvement of various members of splicing kinases, especially SRPKs in multiple cellular processes including proliferation and angiogenesis. 29,30 Overexpression of splicing factors (SRSF1, SRSF2) has been reported in lung, colon and breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

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ABSRTRACTSignaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.

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“…Breast cancer metastasis is a major cause for cancerrelated death in women (Xu et al, 2014), breast cancer metastasis involves the spreading of cancer cells from the primary site to distant sites included lymph node, lungs, liver, bone, and brain. However, the etiology of breast cancer metastasis is unclear and its diagnosis markers are also rare.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of TET1 Promoter Is a New Diagnosic Marker for Breast Cancer Metastasis

Sang

Cheng²,

Tang³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Breast cancer metastasis is a major cause of cancer-related death in women. However, markers for diagnosis of breast cancer metastasis are rare. Here, we reported that TET1, a tumor suppressor gene, was downregulated and hypermethylated in highly metastatic breast cancer cell lines. Moreover, silencing of TET1 in breast cancer cells increased the migration and spreading of breast cancer cells. In breast cancer clinical samples, TET1 expression was reduced in LN metastases compared with primary tissues. Besides, the methylation level of the TET1 promoter was increased significantly in LN metastases. Taken together, these findings indicate that promoter hypermethylation may contribute to the downregulation of TET1 and could be used as a promising marker for diagnosis in patients with breast cancer metastasis.

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Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Cited by 207 publications

References 65 publications

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

A self‐enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Hypermethylation of TET1 Promoter Is a New Diagnosic Marker for Breast Cancer Metastasis

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