Special Issue "RASSF Signalling in Cancer"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 December 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Reinhard Dammann (Website)

Institut für Genetik, Justus-Liebig-Universität Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germary
Interests: RASSF, epigenetics, carcinogenesis, DNA methylation, signaling, gene regulation, tumor suppressor

Special Issue Information

Dear Colleagues,

The Ras Association Domain Family (RASSF) consists of ten members, which encode either a C-Terminal Ras association (RA) domain or a N-terminal RA. Most of the RASSF are tumor suppressor genes that are frequently epigenetically inactivated in human cancers. Functional studies have shown that RASSF signaling is involved in several pathways including Ras and Hippo. Deregulation of the RASSF members alters cell cycle control, growth and apoptosis of cancer cells. Thus aberrant RASSF signaling plays a key role in the pathogenesis of human cancers. In this special issue of cancers we invite you to submit an original manuscript analyzing the function or epigenetic alteration of the RASSF members in cancers.

Prof. Dr. Reinhard Dammann
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • ras Association Domain Family
  • N-Terminal RASSF
  • C-Terminal RASSF
  • cancer
  • epigenetic regulation
  • DNA methylation
  • tumor suppressor gene
  • hippo pathway
  • ras signaling
  • apoptosis
  • cell cycle regulation
  • growth inhibition
  • DNA repair
  • genetic alterations
  • biomarker

Published Papers (7 papers)

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Research

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Open AccessArticle RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1
Cancers 2016, 8(6), 55; doi:10.3390/cancers8060055
Received: 18 March 2016 / Revised: 22 May 2016 / Accepted: 31 May 2016 / Published: 10 June 2016
Cited by 1 | PDF Full-text (8002 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, [...] Read more.
Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the expression relationship between RASSF1A and its downstream target, modulator of apoptosis 1 (MOAP-1), is poorly understood. In this study, we have explored the mRNA expression of RASSF1A, MOAP-1 and the well-characterized splice variant of RASSF1, RASSF1C, in cancer cell lines and primary tumors. We confirmed that the RASSF1A promoter is robustly methylated within a 32-CpG region in solid tumors and results in lower mRNA expression. The MOAP-1 promoter contains ~110 CpG sites, but was not found to be methylated in cancer cell lines when 19 predicted CpG sites were explored. Interestingly, MOAP-1 mRNA expression positively correlated with RASSF1A expression in numerous cancers, whereas RASSF1C expression remained the same or was increased in cell lines or tissues with epigenetic loss of RASSF1A. We speculate that MOAP-1 and RASSF1A may be more intimately connected than originally thought, and the expression of both are warranted in experimental designs exploring the biology of the RASSF1A/MOAP-1 molecular pathway. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
Open AccessArticle NORE1A Regulates MDM2 Via β-TrCP
Cancers 2016, 8(4), 39; doi:10.3390/cancers8040039
Received: 14 January 2016 / Revised: 9 March 2016 / Accepted: 14 March 2016 / Published: 23 March 2016
Cited by 1 | PDF Full-text (1896 KB) | HTML Full-text | XML Full-text
Abstract
Mouse Double Minute 2 Homolog (MDM2) is a key negative regulator of the master tumor suppressor p53. MDM2 regulates p53 on multiple levels, including acting as an ubiquitin ligase for the protein, thereby promoting its degradation by the proteasome. MDM2 is oncogenic [...] Read more.
Mouse Double Minute 2 Homolog (MDM2) is a key negative regulator of the master tumor suppressor p53. MDM2 regulates p53 on multiple levels, including acting as an ubiquitin ligase for the protein, thereby promoting its degradation by the proteasome. MDM2 is oncogenic and is frequently found to be over-expressed in human tumors, suggesting its dysregulation plays an important role in human cancers. We have recently found that the Ras effector and RASSF (Ras Association Domain Family) family member RASSF5/NORE1A enhances the levels of nuclear p53. We have also found that NORE1A (Novel Ras Effector 1A) binds the substrate recognition component of the SCF-ubiquitin ligase complex β-TrCP. Here, we now show that NORE1A regulates MDM2 protein levels by targeting it for ubiquitination by SCF-β-TrCP. We also show the suppression of NORE1A protein levels enhances MDM2 protein expression. Finally, we show that MDM2 can suppress the potent senescence phenotype induced by NORE1A over-expression. Thus, we identify a mechanism by which Ras/NORE1A can modulate p53 protein levels. As MDM2 has several important targets in addition to p53, this finding has broad implications for cancer biology in tumor cells that have lost expression of NORE1A due to promoter methylation. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
Open AccessArticle Proteomics Analysis Reveals Novel RASSF2 Interaction Partners
Cancers 2016, 8(3), 37; doi:10.3390/cancers8030037
Received: 14 January 2016 / Revised: 18 February 2016 / Accepted: 9 March 2016 / Published: 16 March 2016
Cited by 1 | PDF Full-text (1865 KB) | HTML Full-text | XML Full-text
Abstract
RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but [...] Read more.
RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but it likely acts as a scaffolding protein, modulating the activity of other pro-apoptotic effectors, thereby regulating and integrating tumor suppressor pathways. However, only a limited number of RASSF2 interacting partners have been identified to date. We used a proteomics based approach to identify additional RASSF2 interactions, and thereby gain a better insight into the mechanism of action of RASSF2. We identified several proteins, including C1QBP, Vimentin, Protein phosphatase 1G and Ribonuclease inhibitor that function in diverse biological processes, including protein post-translational modifications, epithelial-mesenchymal transition, cell migration and redox homeostasis, which have not previously been reported to interact with RASSF2. We independently validated two of these novel interactions, C1QBP and Vimentin and found that the interaction with C1QBP was enhanced by K-Ras whereas, interestingly, the Vimentin interaction was reduced by K-Ras. Additionally, RASSF2/K-Ras regulated the acetylation of Vimentin. Our data thus reveal novel mechanisms by which RASSF2 may exert its functions, several of which may be Ras-regulated. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
Open AccessFeature PaperArticle Aberrant Promoter Methylation of the Tumour Suppressor RASSF10 and Its Growth Inhibitory Function in Breast Cancer
Cancers 2016, 8(3), 26; doi:10.3390/cancers8030026
Received: 8 December 2015 / Revised: 3 February 2016 / Accepted: 19 February 2016 / Published: 25 February 2016
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Abstract
Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). [...] Read more.
Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby promotes cancer development and progression. In this study we analysed the tumour suppressors RASSF1A and RASSF10. Our study shows that RASSF10 is expressed in normal breast but inactivated by methylation in breast cancer. We observed a significant inactivating promoter methylation of RASSF10 in primary breast tumours. RASSF10 is inactivated in 63% of primary breast cancer samples but only 4% of normal control breast tissue is methylated (p < 0.005). RASSF1A also shows high promoter methylation levels in breast cancer of 56% vs. 8% of normal tissue (p < 0.005). Interestingly more than 80% of breast cancer samples harboured a hypermethylation of RASSF10 and/or RASSF1A promoter. Matching samples exhibited a strong tumour specific promoter methylation of RASSF10 in comparison to the normal control breast tissue. Demethylation treatment of breast cancer cell lines MCF7 and T47D reversed RASSF10 promoter hypermethylation and re-established RASSF10 expression. In addition, we could show the growth inhibitory potential of RASSF10 in breast cancer cell lines MCF7 and T47D upon exogenous expression of RASSF10 by colony formation. We could further show, that RASSF10 induced apoptotic changes in MCF7 and T47D cells, which was verified by a significant increase in the apoptotic sub G1 fraction by 50% using flow cytometry for MCF7 cells. In summary, our study shows the breast tumour specific inactivation of RASSF10 and RASSF1A due to DNA methylation of their CpG island promoters. Furthermore RASSF10 was characterised by the ability to block growth of breast cancer cell lines by apoptosis induction. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
Open AccessArticle lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK
Cancers 2014, 6(2), 879-896; doi:10.3390/cancers6020879
Received: 6 May 2013 / Revised: 12 March 2014 / Accepted: 25 March 2014 / Published: 16 April 2014
Cited by 4 | PDF Full-text (1942 KB) | HTML Full-text | XML Full-text
Abstract
In both Drosophila and mammalian systems, the Hippo (Hpo) signalling pathway controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core pathway consists of a protein kinase Hpo (MST1/2 in mammals) that is regulated by a number of upstream inputs [...] Read more.
In both Drosophila and mammalian systems, the Hippo (Hpo) signalling pathway controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core pathway consists of a protein kinase Hpo (MST1/2 in mammals) that is regulated by a number of upstream inputs including Drosophila Ras Association Factor, dRASSF. We have previously shown in the developing Drosophila eye epithelium that loss of the apico-basal cell polarity regulator lethal-(2)-giant-larvae (lgl), and the concomitant increase in aPKC activity, results in ectopic proliferation and suppression of developmental cell death by blocking Hpo pathway signalling. Here, we further explore how Lgl/aPKC interacts with the Hpo pathway. Deregulation of the Hpo pathway by Lgl depletion is associated with the mislocalization of Hpo and dRASSF. We demonstrate that Lgl/aPKC regulate the Hpo pathway independently of upstream inputs from Fat/Dachs and the Kibra/Expanded/Merlin complex. We show depletion of Lgl also results in accumulation and mislocalization of components of the dSTRIPAK complex, a major phosphatase complex that directly binds to dRASSF and represses Hpo activity. However, depleting dSTRIPAK components, or removal of dRASSF did not rescue the lgl/ or aPKC overexpression phenotypes. Thus, Lgl/aPKC regulate Hpo activity by a novel mechanism, independently of dRASSF and dSTRIPAK. Surprisingly, removal of dRASSF in tissue with increased aPKC activity results in mild tissue overgrowth, indicating that in this context dRASSF acts as a tumor suppressor. This effect was independent of the Hpo and Ras Mitogen Activated Protein Kinase (MAPK) pathways, suggesting that dRASSF regulates a novel pathway to control tissue growth. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
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Review

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Open AccessReview RASSF6; the Putative Tumor Suppressor of the RASSF Family
Cancers 2015, 7(4), 2415-2426; doi:10.3390/cancers7040899
Received: 2 November 2015 / Revised: 1 December 2015 / Accepted: 1 December 2015 / Published: 9 December 2015
PDF Full-text (1353 KB) | HTML Full-text | XML Full-text
Abstract
Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are [...] Read more.
Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are referred to as the C-RASSF proteins. The C-RASSF proteins have the RA domain in the middle region and the Salvador/RASSF/Hippo domain in the C-terminal region. RASSF6 additionally harbors the PSD-95/Discs large/ZO-1 (PDZ)-binding motif. Expression of RASSF6 is epigenetically suppressed in human cancers and is generally regarded as a tumor suppressor. RASSF6 induces caspase-dependent and -independent apoptosis. RASSF6 interacts with mammalian Ste20-like kinases (homologs of Drosophila Hippo) and cross-talks with the Hippo pathway. RASSF6 binds MDM2 and regulates p53 expression. The interactions with Ras and Modulator of apoptosis 1 (MOAP1) are also suggested by heterologous protein-protein interaction experiments. RASSF6 regulates apoptosis and cell cycle through these protein-protein interactions, and is implicated in the NF-κB and JNK signaling pathways. We summarize our current knowledge about RASSF6 and discuss what common and different properties RASSF6 and the other C-RASSF proteins have. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)
Open AccessReview Ras and Rheb Signaling in Survival and Cell Death
Cancers 2013, 5(2), 639-661; doi:10.3390/cancers5020639
Received: 1 April 2013 / Revised: 8 May 2013 / Accepted: 17 May 2013 / Published: 28 May 2013
Cited by 5 | PDF Full-text (540 KB) | HTML Full-text | XML Full-text
Abstract
One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known [...] Read more.
One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively. Full article
(This article belongs to the Special Issue RASSF Signalling in Cancer)

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