Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

Tajiri, H.; Uruno, Takehito; Shirai, Takahiro; Takaya, Daisuke; Matsunaga, Shigeki; Setoyama, Daiki; Watanabe, Masayoshi; Kukimoto-Niino, Mutsuko; Oisaki, Kounosuke; Ushijima, Masahiro; Sanematsu, Fumiyuki; Honma, Teruki; Terada, Takaho; Oki, Eiji; Shirasawa, Senji; Maehara, Yoshihiko; Kang, Dongchon; Côté, Jean; Yokoyama, Shigeyuki; Kanai, Motomu; Fukui, Yoshihiro

doi:10.1016/j.celrep.2017.04.016

Cited by 54 publications

(52 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others previously demonstrated that Rac GTPases regulate myeloid leukemia cell survival and engraftment in vivo (46, 47). Importantly, DOCK proteins play a key role in Ras‐mediated activation of the Rac pathway, which promotes cancer cell survival (48). We asked whether MBD3‐mediated regulation of DOCK is of potential clinical significance.…”

Section: Resultsmentioning

confidence: 99%

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

et al. 2019

View full text Add to dashboard Cite

Cancer genome sequencing studies have focused on identifying oncogenic mutations. However, mutational profiling alone may not always help dissect underlying epigenetic dependencies in tumorigenesis. Nucleosome remodeling and deacetylase (NuRD) is an ATP‐dependent chromatin remodeling complex that regulates transcriptional architecture and is involved in cell fate commitment. We demonstrate that loss of MBD3, an important NuRD scaffold, in human primary acute myeloid leukemia (AML) cells associates with leukemic NuRD. Interestingly, CHD4, an intact ATPase subunit of leukemic NuRD, coimmunoprecipitates and participates with H3K27Me3/2‐demethylase KDM6A to induce expression of atypical guanine nucleotide exchange factors, dedicator of cytokinesis (DOCK) 5 and 8 (DOCK5/8), promoting Rae GTPase signaling. Mechanistically, MBD3 deficiency caused loss of histone deacytelase 1 occupancy with a corresponding increase in KDM6A, CBP, and H3K27Ac on DOCK5/8 loci, leading to derepression of gene expression. Importantly, the Cancer Genome Atlas AML cohort reveals that DOCK5/8 levels are correlated with MBD3 and KDM6A, and DOCK5/8 expression is significantly increased in patients who are MBD3 low and KDM6A high with a poor survival. In addition, pharmacological inhibition of DOCK signaling selectively attenuates AML cell survival. Because MBD3 and KDM6A have been implicated in metastasis, our results may suggest a general phenomenon in tumorigenesis. Collectively, these findings provide evidence for MBD3‐deficient NuRD in leukemia pathobiology and inform a novel epistasis between NuRD and KDM6A toward maintenance of oncogenic gene expression in AML.—Biswas, M., Chatterjee, S. S., Boila, L. D., Chakraborty, S., Banerjee, D., Sengupta, A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rae GTPase activation in human acute myeloid leukemia. FASEB J. 33, 5268–5286 (2019). http://www.fasebj.org

show abstract

Section: Resultsmentioning

confidence: 99%

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Such evidence of an oncogenic and metastasis promoting role for DOCK family members has led to an interest in the development of DOCK inhibitors. TBOPP, a DOCK1 selective inhibitor, inhibited tumor growth and metastasis in mice with lung carcinoma tumors (Tajiri et al, 2017). This compound also targeted DOCK1 in melanoma cells with the oncogenic Rac1 P29S mutation (Tomino et al, 2018).…”

Section: Targeting Docksmentioning

confidence: 99%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

show abstract

“…DOCK5 is a highly specific GEF for Rac1 GTPase, which is the major function of this protein [3,33,34]. Although whether the interaction between Rac1 and mTOR depends on its GDP/GTP loading state is still controversial, Rac 1 is critical for mTOR signaling regulation in both mTORC1 and mTORC2 [16,[35][36][37].…”

mentioning

confidence: 99%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

View full text Add to dashboard Cite

The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

show abstract

Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

Cited by 54 publications

References 46 publications

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

Contact Info

Product

Resources

About