RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis

Ren, Kehan; Zhou, Danmei; Wang, Meili; Li, Ermin; Hou, Changbo; Su, Ying; Zou, Qiang; Zhou, Ping; Liu, Xiuping

doi:10.1016/j.yexcr.2021.112493

Cited by 43 publications

(29 citation statements)

References 51 publications

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“…Two recent studies look at how RAC GTPase activation protein 1 (RACGAP1) influences metastasis through ERK dependent mitochondrial fission and quality control ( Ren et al, 2021 ; Zhou et al, 2021 ). RACGAP1 contains a conserved Rho GAP domain which facilitates the inactivation of small GTPases of the Rho family including RAC1, CDC42, and RHOA ( Touré et al, 1998 ).…”

Section: Introductionmentioning

confidence: 99%

“…RACGAP1 contains a conserved Rho GAP domain which facilitates the inactivation of small GTPases of the Rho family including RAC1, CDC42, and RHOA ( Touré et al, 1998 ). In breast cancer, RACGAP1 mRNA is expressed higher in tumorigenic tissue in comparison to normal tissue, and higher expression of RACGAP1 leads to a worse overall survival ( Ren et al, 2021 ). Intravenous tail injection of RACGAP1 overexpressing cells in MCF7 increased lung metastasis in comparison to control cells.…”

Section: Introductionmentioning

confidence: 99%

“…Invasive capacity of RACGAP1 overexpressing cells could be reduced via pharmacological elongation of the mitochondrial pool. Mechanistically it was found that pERK1/2 and pDRP1 increased with overexpression RACGAP1, both of which could be reduced via MEK inhibition ( Ren et al, 2021 ). Strengthening this, MEK inhibition increased mitochondrial and subsequently decreased invasive capacity in a dose dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

Boulton

Caino

2022

Front. Cell Dev. Biol.

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Mitochondria are highly dynamic organelles which can change their shape, via processes termed fission and fusion, in order to adapt to different environmental and developmental contexts. Due to the importance of these processes in maintaining a physiologically healthy pool of mitochondria, aberrant cycles of fission/fusion are often seen in pathological contexts. In this review we will discuss how dysregulated fission and fusion promote tumor progression. We focus on the molecular mechanisms involved in fission and fusion, discussing how altered mitochondrial fission and fusion change tumor cell growth, metabolism, motility, and invasion and, finally how changes to these tumor-cell intrinsic phenotypes directly and indirectly impact tumor progression to metastasis. Although this is an emerging field of investigation, the current consensus is that mitochondrial fission positively influences metastatic potential in a broad variety of tumor types. As mitochondria are now being investigated as vulnerable targets in a variety of cancer types, we underscore the importance of their dynamic nature in potentiating tumor progression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

Boulton

Caino

2022

Front. Cell Dev. Biol.

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“…Furthermore, Zhao has found that depletion of RACGAP1 could lead to mitotic catastrophe and massive cell death in esophageal squamous cell carcinoma (33). Kehan confirmed that RACGAP1 played an essential role in breast cancer metastasis by modulating ECT2-dependent mitochondrial quality control (34). Yong found that RACGAP1 overexpression was significantly related to poor prognosis in HCC patients, and could promote proliferation ability of HCC cells via inhibiting activation of the Hippo and YAP pathways (35).…”

Section: Discussionmentioning

confidence: 95%

A Novel Five-Gene Signature for Prognosis Prediction in Hepatocellular Carcinoma

Zhang

Kong

2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) has been a global health issue and attracted wide attention due to its high incidence and poor outcomes. In this study, our purpose was to explore an effective prognostic marker for HCC. Five cohort profile datasets from GEO (GSE25097, GSE36376, GSE62232, GSE76427 and GSE101685) were integrated with TCGA-LIHC and GTEx dataset to identify differentially expressed genes (DEGs) between normal and cancer tissues in HCC patients, then 5 upregulated differentially expressed genes and 32 downregulated DEGs were identified as common DEGs in total. Next, we systematically explored the relationship between the expression of 37 common DEGs in tumor tissues and overall survival (OS) rate of HCC patients in TCGA and constructed a novel prognostic model composed of five genes (AURKA, PZP, RACGAP1, ACOT12 and LCAT). Furthermore, the predicted performance of the five-gene signature was verified in ICGC and another independent clinical samples cohort, and the results demonstrated that the signature performed well in predicting the OS rate of patients with HCC. What is more, the signature was an independent hazard factor for HCC patients when considering other clinical factors in the three cohorts. Finally, we found the signature was significantly associated with HCC immune microenvironment. In conclusion, the prognostic five-gene signature identified in our present study could efficiently classify patients with HCC into subgroups with low and high risk of longer overall survival time and help clinicians make decisions for individualized treatment.

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“…In basal-like breast cancer, depletion of RACGAP1 impaired cell growth via partly resulting from p21-induction and onset of senescence 9 . A recent study on breast cancer revealed that RACGAP1 promotes mitochondrial dynamic driven metastasis through recruiting ECT2 and subsequently activating ERK-DRP1 pathway 29 . Here, we found that RACGAP1 expression was upregulated in human GBC tissues.…”

Section: Discussionmentioning

confidence: 99%

Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis

Bian¹,

Dang²,

Song³

et al. 2021

Int. J. Biol. Sci.

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Rac GTPase activating protein 1 (RACGAP1) has been characterized in the pathogenesis and progression of several malignancies, however, little is known regarding its role in the development of gallbladder cancer (GBC). This investigation seeks to describe the role of RACGAP1 and its associated molecular mechanisms in GBC. It was found that RACGAP1 was highly expressed in human GBC tissues, which was associated to poorer overall survival (OS). Gene knockdown of RACGAP1 hindered tumor cell proliferation and survival both in vitro and in vivo . We further identified that RACGAP1 was involved in DNA repair through its binding with DNA ligase 3 (LIG3), a crucial component of the alternative-non-homologous end joining (Alt-NHEJ) pathway. RACGAP1 regulated LIG3 expression independent of RhoA activity. RACGAP1 knockdown resulted in LIG3-dependent repair dysfunction, accumulated DNA damage and Poly(ADP-ribosyl) modification (PARylation) enhancement, leading to increased apoptosis and suppressed cell growth. We conclude that RACGAP1 exerts a tumor-promoting role via binding LIG3 to reduce apoptosis and facilitate cell growth in GBC, pointing to RACGAP1 as a potential therapeutic target for GBC.

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RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis

Cited by 43 publications

References 51 publications

Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

A Novel Five-Gene Signature for Prognosis Prediction in Hepatocellular Carcinoma

Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis

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