Transforming mutations of RAC guanosine triphosphatases in human cancers

Kawazu, Masahito; Ueno, Toshihide; Kontani, Kenji; Ogita, Yoshitaka; Ando, Mizuo; Fukumura, Kazutaka; Yamato, Azusa; Soda, Manabu; Takeuchi, Kengo; Miki, Yoshio; Yamaguchi, Hiroyuki; Yasuda, Takahiko; Naoe, Tomoki; Yamashita, Yuichi; Katada, Toshiaki; Choi, Young Lim; Mano, Hiroyuki

doi:10.1073/pnas.1216141110

Cited by 107 publications

(117 citation statements)

References 23 publications

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“…The antiproliferative activity of wild-type ELF4 was also apparent in HT1080 cells (Fig. 1C), which do not harbor any nonsynonymous mutations within ELF1, ELF2, or ELF4 (22). In this cell line, however, ELF4 (L211M) had a moderate antiproliferative effect, likely reflecting its residual transactivation activity (Fig.…”

Section: Resultsmentioning

confidence: 88%

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

et al. 2016

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ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted antiproliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial. Cancer Res; 76(7); 1814-24. Ó2016 AACR.

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Section: Resultsmentioning

confidence: 88%

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

et al. 2016

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“…S2A). PI3Kb is thought to be involved in signaling downstream of certain GCPRs and mutant rac (16). To further assess signaling via the LPA receptor pathway, inhibition in the PTEN WT mutant rac lines HT1080 and MDA-MB-157 was assessed.…”

Section: Resultsmentioning

confidence: 99%

“…PI3Kb activation by GPCRs for LPA, SIP, and thrombin via rac /DOCK180 (15) may also be important in these lines. Interestingly, one of the more sensitive lines, MDA-MB-157, expressed mutant rac (16). Loss of PTEN expression is common across many tumor types, TNBC (9), prostate (10,11), head and neck (21), colorectal cancer (22,23), and squamous lung (24), suggesting that inhibitors of PI3Kb are relevant in many diseases.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.

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“…They also identify MKL1 as a novel gatekeeper in the regulation of adipogenesis as well as provide a basis for further studies of the relation between the dynamics of cell shape and transcription factor function during cellular differentiation. Lastly, given that activating mutations of RAC protein, which belongs to the RHO family of small GTPases and orchestrates actin polymerization, were found in a wide variety of human cancers and given their marked transforming ability 38 , we assume that aberrant differentiation associated with actin cytoskeleton dynamics can be a critical factor of tumorigenesis, and our works thus would potentially contribute to understanding cancer biology.…”

Section: Discussionmentioning

confidence: 99%

Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

et al. 2014

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Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator-activated receptor g (PPARg), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARg followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARg act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation.

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Transforming mutations of RAC guanosine triphosphatases in human cancers

Cited by 107 publications

References 23 publications

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

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