RHAMM Promotes Interphase Microtubule Instability and Mitotic Spindle Integrity through MEK1/ERK1/2 Activity

Tölg, Cornelia; Hamilton, Sara R.; Morningstar, Lyndsey; Zhang, Jing; Zhang, S.; Esguerra, Kenneth Virgel N.; Telmer, Patrick G.; Luyt, Leonard G.; Harrison, Rene E.; McCarthy, James B.; Turley, Eva A.

doi:10.1074/jbc.m110.121491

Cited by 83 publications

(105 citation statements)

References 60 publications

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“…RHAMM functions as cell-surface HA receptor and cytoplasmic mitotic spindle binding protein (4,5). It mediates tumor progression through CD44 partnership and promotes genomic instability via regulating the mitotic spindle/centrosome integrity (18,19). This RHAMMregulated activation process results in increased cell-surface expression of CD44 and enhanced activation of ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of RHAMM causes transformation and promotes breast cancer cell migration and invasion (BCCMI), and its expression is up-regulated in a variety of human tumors, including breast and endometrial carcinomas (6)(7)(8), gastrointestinal cancers (9, 10), prostate cancer (11), aggressive fibromatosis (i.e., desmoid tumor) (12), lung and liver cancer (13,14), glioma (15), and B-cell malignancies (16,17). RHAMM binds to mitotic spindles and promotes interphase microtubule instability and mitotic spindle integrity (18,19). Uniquely, it is also unconventionally exported onto extracellular surface to partner with CD44, thereby enhancing CD44-mediated tumor progression via ERK1/2 association, and maintaining high proliferative activities and motility of invasive cancer cells (20,21).…”

mentioning

confidence: 99%

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Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

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

276

284

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Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

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

276

284

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“…HMMR is distributed in both the cytoplasm and nucleus and functions as a cell surface receptor for HA. In addition, HMMR is a centrosomal protein that contributes to the stability of the mitotic spindle (16,17). In addition, HMMR also regulates the G 2 /M phase in the cell cycle (16).…”

mentioning

confidence: 99%

Mechanism of MTA1 Protein Overexpression-linked Invasion

Sankaran

Pakala

Nair

et al. 2012

Journal of Biological Chemistry

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Background: Although MTA1 is overexpressed in advanced human cancer, its role in cancer invasion and migration needs to be elucidated. Results: MTA1 transcriptionally stimulates expression of the hyaluronan-mediated motility receptor (HMMR) and consequently regulates cancer invasion and migratory function. Conclusion: HMMR is a mediator of MTA1-mediated invasion and motility. Significance: This is the first report connecting MTA1 with HMMR expression and function.

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“…In mesenchymal cells, the absence of RHAMM increases microtubule stability resulting in reduced cell migration and aberrant mitotic spindle formation (Tolg et al, 2010, Groen et al, 2004. RHAMM interacts directly with ERK1, inferring that RHAMM may act as a scaffolding protein that directs ERK1 to its substrates including microtubule associated proteins that regulate microtubule stability (Tolg et al, 2010). Interestingly, RHAMM expression is downregulated by p53, an important tumour suppressor gene, suggesting that RHAMM may be involved in p53 loss-induced tumour progression (Buganim and Rotter, 2008, Godar and Weinberg, 2008, Sohr and Engeland, 2008.…”

Section: Rhamm/hmmrmentioning

confidence: 99%

“…Intracellularly, RHAMM binds directly to tubulin and is involved in regulation of microtubule stability and turnover as a result of its association with ERK1,2. In mesenchymal cells, the absence of RHAMM increases microtubule stability resulting in reduced cell migration and aberrant mitotic spindle formation (Tolg et al, 2010, Groen et al, 2004. RHAMM interacts directly with ERK1, inferring that RHAMM may act as a scaffolding protein that directs ERK1 to its substrates including microtubule associated proteins that regulate microtubule stability (Tolg et al, 2010).…”

Section: Rhamm/hmmrmentioning

confidence: 99%

Hyaluronan Associated Inflammation and Microenvironment Remodelling Influences Breast Cancer Progression

Ward¹,

Vásquez²,

Tölg³

et al. 2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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RHAMM Promotes Interphase Microtubule Instability and Mitotic Spindle Integrity through MEK1/ERK1/2 Activity

Cited by 83 publications

References 60 publications

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Mechanism of MTA1 Protein Overexpression-linked Invasion

Hyaluronan Associated Inflammation and Microenvironment Remodelling Influences Breast Cancer Progression

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