CD44 acts through RhoA to regulate YAP signaling

Zhang, Yuchen; Xiao, Hong‐Wei; Ge, Xianping; Chen, Qingjuan; Yuan, Dandan; Chen, Qi; Leng, Weibing; Chen, Liang; Tang, Qiulin; Bi, Feng

doi:10.1016/j.cellsig.2014.07.031

Cited by 60 publications

(66 citation statements)

References 51 publications

(69 reference statements)

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“…CD44 is a direct and functional target of miR-34a as CD44 knockdown phenocopies miR-34a overexpression in inhibiting the metastasis of prostate cancer cells (25). CD44 is a cell-surface adhesion glycoprotein involved in cellular adhesion, migration and apoptosis resistance, and is highly expressed in numerous cancer cells (26). CD44 indirectly links to actin by interacting with ERM proteins (ezrin, radixin and moesin) (27).…”

Section: Discussionmentioning

confidence: 99%

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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Abstract. Overexpression of histone deacetylases (HDACs) is associated with higher metastatic rates and a poor prognosis in gastric cancer. However, the underlying mechanisms involved remain unclear. The present study aimed to investigate the molecular pathways that are involved in HDAC1-mediated metastatic activities in gastric cancer cells. First we used a microRNA (miRNA or miR) microarray to screen potential miRNAs whose expression can be altered by HDAC1 depletion. Of these miRNAs, miR-34a is important as it is often inactivated in cancer cells and acts as a tumor suppressor for various types of cancer. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that miR-34a was upregulated by HDAC1 knockdown. Cells depleted of HDAC1 had lower abilities to migrate, invade and adhere, which were restored by a miR-34a antagomiR. Depletion of HDAC1 also resulted in impaired microfilaments and microtubules, while co-transfection of the miR-34a antagomiR attenuated these changes in the cellular cytoskeleton. The HDAC1/miR-34a axis regulated the expression and activation of CD44 and its downstream factors including Bcl-2, Ras homolog family member A (RhoA), LIM domain kinase 1 (LIMK-1) and matrix metalloproteinase (MMP)-2. The latter three proteins were responsible for the organization of tubulin and actin cytoskeleton and the formation of cellular pseudopodia. In conclusion, results of the present study indicated that HDAC1 depletion inhibits the metastatic abilities of gastric cancer cells by regulating the miRNA-34a/CD44 pathway, which may be a potential target for the treatment of gastric cancer. IntroductionGastric cancer remains the fourth most common malignancy and the second leading cause of cancer-related mortality worldwide, although its incidence is gradually on the decrease in most parts of the world (1). The currently available chemotherapeutic agents have only limited benefits for most gastric cancer patients. Therefore, identification of novel targets and an understanding of their molecular mechanisms is crucial for the treatment of gastric cancer patients.Histone deacetylases (HDACs) are a class of enzymes that remove the acetyl groups from core histones, as well as non-histone proteins, such as p53 (2). By modifying the status of deacetylation, HDACs induce transcriptional repression through chromatin condensation and alteration of protein activity (3). Among the 18 HDAC family members, HDAC1 accounts for more than half of cellular HDAC activity, and cannot be compensated by other HDACs (4). HDAC1 acts at all levels of gene expression including microRNA (miRNA or miR) regulation (5). Overexpression of HDAC1 is significantly associated with higher lymphatic metastases and decreased 3-year survival rates in gastric cancer patients (6). Many HDAC inhibitors have been developed, several of which have shown promise and are under investigation in clinical trials (3,7). However, the underlying mechanisms for the anti-metastatic activities of HDAC inhibitors, particularly...

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Section: Discussionmentioning

confidence: 99%

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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“…After Merlin dissociation, CD44 regulates YAP expression via RhoA, which results in increased apoptosis resistance (Takahashi et al, 2010; Xu et al, 2010) (Figure 3D). In a feedback loop, activated YAP binds to the RHAMM promoter inducing RHAMM transcription (Lynch et al, 2007; Zhang Y. et al, 2014). …”

Section: Linking Cd44/cd44v6 Activities To Cic Featuresmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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“…Previously, we showed that RHOA knockdown reduced ovarian cancer cell proliferation, promoted apoptosis, and suppressed lamellipodia formation and cell migration and invasion by downregulating the relevant genes, including that for P70S6K and Bcl-xL [6]. YAP is the major downstream cascade of Hippo signaling, designated the Hippo-YAP pathway, and has been identified as a candidate oncogene [15][16][17][18][19], Zhang et al showed that RhoA knockdown mediated YAP downregulation, promoting apoptosis and inhibiting cell proliferation, cell cycle progression, and migration [20]. As reviewed by Hall [21], RhoA exerts multiple functions in tumor metastasis by orchestrating the action of multiple downstream effectors and promoting extracellular matrix degradation and reconstruction; Fagan-Solis et al showed that blocking RhoA activity inhibited the invasive behavior of breast cancer cells by inhibiting MMP2 and MMP9 directly [22].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

LncRNA PCGEM1 Induces Ovarian Carcinoma Tumorigenesis and Progression Through RhoA Pathway

Chen¹,

Wang²,

Sun³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Prostate cancer gene expression marker 1 (PCGEM1) is a long noncoding RNA (lncRNA) and is well known as a promoter in prostate cancer and osteoarthritis synoviocytes. However, the role PCGEM1 plays in epithelial ovarian cancer is unknown. Methods: PCGEM1 expression was examined in epithelial ovarian cancer and normal ovarian tissues using reverse transcription–PCR. Ovarian cancer cell phenotypes and genotypes were examined after PCGEM1 overexpression or downregulation in vitro; besides, the effects of PCGEM1 overexpression was also examined in vivo. Results: PCGEM1 expression level was higher in epithelial ovarian cancer tissues than in normal ovarian tissues and was positively associated with differentiation (Well vs. Mod/Poor). Upregulation of PCGEM1 induced cancer cell proliferation, migration, and invasion, but decreased cell apoptosis through upregulating RhoA, YAP (Yes-associated protein), MMP2 (matrix metalloproteinase 2), Bcl-xL, and P70S6K expression; while PCGEM1 downregulation had the opposite effect. The nude mouse xenograft assay demonstrated that PCGEM1 overexpression promoted tumor growth. Furthermore, silencing RhoA expression reversed the effect of PCGEM1 and significantly inhibited RhoA, YAP, MMP2, Bcl-xL, and P70S6K protein expression. Conclusion: In conclusion, we suggest that PCGEM1 may be an inducer in epithelial ovarian cancer tumorigenesis and progression by upregulating RhoA and the subsequent expression of YAP, P70S6K, MMP2, and Bcl-xL.

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CD44 acts through RhoA to regulate YAP signaling

Cited by 60 publications

References 51 publications

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

LncRNA PCGEM1 Induces Ovarian Carcinoma Tumorigenesis and Progression Through RhoA Pathway

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