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A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness.

ABSTRACT: The switch between stem/progenitor cell expansion and differentiation is critical for organ homeostasis. The mammalian Hippo pathway effector and oncoprotein YAP expands undifferentiated stem/progenitor cells in various tissues. However, the YAP-associated transcription factors and downstream targets underlying this stemness-promoting activity are poorly understood. Here we show that the SRF-IL6 axis is the critical mediator of YAP-induced stemness in mammary epithelial cells and breast cancer. Specifically, serum response factor (SRF)-mediated binding and recruitment of YAP to mammary stem cell (MaSC) signature-gene promoters induce numerous MaSC signature genes, among which the target interleukin (IL)-6 is critical for YAP-induced stemness. High SRF-YAP/TAZ expression is correlated with IL6-enriched MaSC/basal-like breast cancer (BLBC). Finally, we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer. Collectively, our results establish the importance of SRF-YAP-IL6 signalling in promoting MaSC-like properties in a BLBC-specific manner.

SUBMITTER: Kim T

PROVIDER: S-EPMC4703869 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness.

Kim Tackhoon T Yang Suk-Jin SJ Hwang Daehee D Song Jinhoi J Kim Minchul M Kyum Kim Sang S Kang Keunsoo K Ahn Jaebum J Lee Daeyoup D Kim Mi-Young MY Kim Seyun S Seung Koo Ja J Seok Koh Sang S Kim Seon-Young SY Lim Dae-Sik DS

Nature communications 20151216

The switch between stem/progenitor cell expansion and differentiation is critical for organ homeostasis. The mammalian Hippo pathway effector and oncoprotein YAP expands undifferentiated stem/progenitor cells in various tissues. However, the YAP-associated transcription factors and downstream targets underlying this stemness-promoting activity are poorly understood. Here we show that the SRF-IL6 axis is the critical mediator of YAP-induced stemness in mammary epithelial cells and breast cancer. ...[more]

PMID: 26671411

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Project description:Background: Chemoresistance is a significant obstacle to the effective treatment of breast cancer (BC), resulting in more aggressive behavior and worse clinical outcome. The molecular mechanisms underlying breast cancer chemoresistance remain unclear. Our microarray analysis had identified the overexpression of a small molecular glycoprotein serglycin (SRGN) in multidrug-resistant BC cells. Here, we aimed to investigate the role of SRGN in chemoresistance of breast cancer and elucidate the underlying mechanisms. Methods: SRNG overexpression was identified using microarray analysis and its clinical relevance was analyzed. To investigate the role of SRGN, we performed various in vitro and in vivo studies, as well as characterization of serum and tissue samples from BC patients. Chemosensitivity measurement, gene expression interference, immunofluorescence staining, mammosphere assay, flow cytometry analysis, luciferase reporter assay, ChIP-qPCR, coimmunoprecipitation, and immunohistochemistry were performed to explore the potential functions and mechanisms of SRGN. Results: We confirmed overexpression of SRGN in chemoresistant BC cells and in serum and tissue samples from BC patients with poor response to chemotherapy. SRGN specifically predicted poor prognosis in BC patients receiving chemotherapy. Mechanistically, SRGN promoted chemoresistance both in vitro and in vivo by cross-talking with the transcriptional coactivator YES-associated protein (YAP) to maintain stemness in BC cells. Ectopic YAP expression restored the effects of SRGN knockdown. Inversely, YAP knockdown rescued the effects of SRGN overexpression. The secreted SRGN triggered ITGA5/FAK/CREB signaling to enhance YAP transcription. Reciprocally, YAP promoted SRGN transcription in a TEAD1-dependent manner to form a feed-forward circuit. Moreover, the YAP/RUNX1 complex promoted HDAC2 transcription to induce chemoresistance and stemness in BC cells. Importantly, the SRGN levels were positively correlated with the YAP and HDAC2 levels in chemoresistant BC tissues. YAP and HDAC2 acted downstream of SRNG and correlated with poor outcomes of BC patients receiving chemotherapy. Conclusions: Our findings clarify the roles and mechanisms of SRGN in mediating chemoresistance in breast cancer and suggest its use a potential biomarker for chemotherapeutic response. We believe that novel therapeutic strategies for breast cancer can be designed by targeting the signaling mediated by the crosstalk between SRGN and YAP.

Project description:Background: Cancer stem cells (CSCs) have been recognized as an important drug target, however, the underlying mechanisms have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 promotes colorectal cancer (CRC) stem cells (CRC-SCs) and the underlying mechanisms have remained elusive.Methods: Human CRC cell lines and primary human CRC cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels of target genes were examined by qRT-PCR and western blot. The sphere-forming and in vitro migration capacities were determined by sphere formation and transwell assay. The self-renewal was determined by limiting dilution assay. The tumorigenicity and metastasis of cancer cells were examined by xenograft model. The promoter activity was examined by luciferase reporter assay. Nuclear run-on and Chromatin immunoprecipitation-PCR (ChIP-PCR) assay were employed to examine the transcription and protein-DNA interaction. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean?±?SD and the significance was determined by Student's t test.Results: SKP1 was upregulated in CRC-SCs and predicted poor prognosis of colon cancer patients. Overexpression of SKP1 promoted the stemness of CRC cells reflected by increased sphere-forming, migration and self-renewal capacities as well as the expression of CSCs markers. In contrast, SKP1 depletion produced the opposite effects. SKP1 strengthened YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of CRC cells. SKP1 suppressed RASSF1 at both mRNA and protein level. Overexpression of RASSF1 abolished the effect of SKP1 on YAP activity and CRC stemness.Conclusion: Our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of CRC cells.

Dataset Information

A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness.

Publications

A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness.

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