The tumor suppressor RASSF1A induces the YAP1 target gene <i>ANKRD1</i> that is epigenetically inactivated in human cancers and inhibits tumor growth

Jiménez, Adriana P.; Traum, Annalena; Boettger, Thomas; Hackstein, Holger; Richter, Antje; Dammann, Reinhard

doi:10.18632/oncotarget.18177

Cited by 37 publications

(43 citation statements)

References 60 publications

(96 reference statements)

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“…In this signaling network, RASSF1A acts as an upstream activator through its interaction with MST1/2 and WW45 [ 13 , 18 ]. RASSF1A is the only tumor suppressor gene that is frequently inactivated in this pathway [ 19 , 20 , 21 ]. Thus reexpression of RASSF1A induces cell cycle arrest [ 22 , 23 ] and also activates the YAP1 target gene ANKRD1 [ 19 ].…”

Section: The Ras Association Domain Family 1 ( Rassf1 mentioning

confidence: 99%

“…RASSF1A is the only tumor suppressor gene that is frequently inactivated in this pathway [ 19 , 20 , 21 ]. Thus reexpression of RASSF1A induces cell cycle arrest [ 22 , 23 ] and also activates the YAP1 target gene ANKRD1 [ 19 ]. Activation of ANKRD1 was absent in HeLa cells that harbor an unmethylated RASSF1A promoter and express RASSF1A [ 19 ].…”

Section: The Ras Association Domain Family 1 ( Rassf1 mentioning

confidence: 99%

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Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

Dammann

Richter

Jiménez

et al. 2017

IJMS

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Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation.

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Section: The Ras Association Domain Family 1 ( Rassf1 mentioning

confidence: 99%

Section: The Ras Association Domain Family 1 ( Rassf1 mentioning

confidence: 99%

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

Dammann

Richter

Jiménez

et al. 2017

IJMS

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“…Cell lines were transfected for indicated time points using Polyethylenimmin (PEI, 4,9 mM, Sigma) for HEK293 cells. Doxycycline (Dox, Thermo Fisher Scientific) was dissolved in water and used for RASSF10 induction in HEK293 cells within the TetOn-TREx-system at working concentration of 2 µg/ml for 48 h [69].…”

Section: Cell Culture and Treatment Of Cell Linesmentioning

confidence: 99%

RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice

et al. 2020

Self Cite

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Kidney cancer incidences are rising globally, thereby fueling the demand for targeted therapies and precision medicine. In our previous work, we have identified and characterized the Ras-Association Domain Family encoding ten members that are often aberrantly expressed in human cancers. In this study, we created and analyzed the Rassf10 knockout mice. Here we show that Rassf10 haploinsufficiency promotes neoplasia formation in two established mouse cancer models (Rassf1A −/− and p53 −/−). Haploinsufficient Rassf10 knockout mice were significantly prone to various diseases including lymphoma (Rassf1A −/− background) and thymoma (p53 −/− background). Especially Rassf10 −/− and p53-deficient mice exhibited threefold increased rates of kidney cysts compared with p53 −/− controls. Moreover, we observed that in human kidney cancer, RASSF10 is frequently epigenetically inactivated by its CpG island promoter hypermethylation. Primary tumors of renal clear cell and papillary cell carcinoma confirmed that RASSF10 methylation is associated with decreased expression in comparison to normal kidney tissue. In independent data sets, we could validate that RASSF10 inactivation clinically correlated with decreased survival and with progressed disease state of kidney cancer patients and polycystic kidney size. Functionally, we revealed that the loss of Rassf10 was significantly associated with upregulation of KRAS signaling and MYC expression. In summary, we could show that Rassf10 functions as a haploinsufficient tumor suppressor. In combination with other markers, RASSF10 silencing can serve as diagnostic and prognostic cancer biomarker in kidney diseases.

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“…As AKT1 is an inhibitor of FOXO3A [6] and FOXO3A is an inhibitor of ERα activity [21], we also hypothesized that RASSF1A may inhibit ERα through mechanisms that involve activation of FOXO3A. Moreover, RASSF1A can activate the Hippo pathway [24,25] and modify the function of the Hippo-kinase effector YAP1 [26]. YAP1 can activate AKT1 and Skp2 leading to increased degradation of FOXO1/3 [27].…”

Section: Introductionmentioning

confidence: 99%

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A)

Roßwag

Thiede

Sleeman

et al. 2020

Cancers

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The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ERα expression and function in ERα-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ERα expression and activity. Here we report that RASSF1A acts as an inhibitor of ERα-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ERα expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ERα+ breast cancer initiation and progression.

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The tumor suppressor RASSF1A induces the YAP1 target gene ANKRD1 that is epigenetically inactivated in human cancers and inhibits tumor growth

Cited by 37 publications

References 60 publications

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A)

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