Afadin (AF6) in cancer progression: A multidomain scaffold protein with complex and contradictory roles

Huxham, Jennifer; Tabariès, Sébastien; Siegel, Peter M.

doi:10.1002/bies.202000221

Cited by 14 publications

(10 citation statements)

References 138 publications

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“…7 h). Recent research revealed that afadin, an F-actin-binding protein, plays an important role in BC liver metastasis, and a lack of afadin significantly diminished the colony-forming ability of BC cells and metastasis formation in the liver [ 15 , 16 ]. Next, we found that the protein level of afadin was not only correlated with the expression of circROBO1 but also associated with the status of autophagy as assessed by western blot, whereas the mRNA level of afadin remained almost unchanged (Fig.…”

Section: Resultsmentioning

confidence: 99%

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin

Wang

Yang

et al. 2022

Mol Cancer

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Background Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous. Methods In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot. Results In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5. Conclusions Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.

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Section: Resultsmentioning

confidence: 99%

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin

Wang

Yang

et al. 2022

Mol Cancer

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“…As for the TJ formation–promoting activity of LPA in an E-cadherin-based cell adhesion–independent manner in E-cadherin -KO and αE-catenin- KO and the AJC organization–promoting activity of LPA in afadin -KO EpH4 cells, these activities may operate in various cancers in which E-cadherin, αE-catenin, or afadin is lost or downregulated ( 59 , 60 , 61 ). In addition, the reduced activities of E-cadherin, αE-catenin, and afadin have been reported: For instance, inactivating mutations of E-cadherin are frequently detected in infiltrating lobular breast carcinomas and in diffuse gastric cancer ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of lysophosphatidic acid in serum as a factor that promotes epithelial apical junctional complex organization

Sakakibara¹,

Sakane²,

Sasaki³

et al. 2022

Journal of Biological Chemistry

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“…However, it remained elusive how the AJC structure and the apicobasal polarity are impaired in T47D cells stably expressing both nectin-4 and p95-ErbB2. It was noted that these cells were deficient of afadin, and afadin deficiency is observed in many cancer cells, such as colon, breast, pancreatic, osteosarcoma, myometrial cancers, and acute myeloid leukemia (Huxham et al, 2021). It is possible that this afadin deficiency in T47D cells stably expressing both nectin-4 and p95-ErbB2 causes the impaired AJC structure and the apicobasal polarity and multilayered proliferation in an adherent culture.…”

Section: Localizations Of Cell Polarity Molecules In Parental T47d An...mentioning

confidence: 99%

Stimulatory role of nectin‐4 and p95‐ErbB2 in multilayered T47D cell proliferation

et al. 2022

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Multilayered proliferation in an adherent culture as well as proliferation in a suspension culture is a characteristic feature of cancer cells. We previously showed using T47D human mammary cancer cells that nectin-4, upregulated in many cancer cells, cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, p95-ErbB2 and ErbB2ΔEx16, and enhances DNA synthesis mainly through the PI3K-AKT pathway in an adherent culture. We showed here that only the combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and ErbB2 or that of nectin-4 and ErbB2ΔEx16, cooperatively enhanced multilayered T47D cell proliferation through the Hippo pathwaymediated SOX2 gene expression in an adherent culture. T47D cells expressed the components of the apical junctional complex (AJC) consisting of adherens junctions (AJs) and tight junctions and cell polarity molecules, but not the AJ component afadin. The AJC and apicobasal polarity were disorganized in T47D cells in a monolayer and T47D cells stably expressing both nectin-4 and p95-ErbB2 in multilayers. These results indicate that nectin-4 and p95-ErbB2 play a stimulatory role in multilayered proliferation in an adherent culture.

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Afadin (AF6) in cancer progression: A multidomain scaffold protein with complex and contradictory roles

Cited by 14 publications

References 138 publications

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin

Identification of lysophosphatidic acid in serum as a factor that promotes epithelial apical junctional complex organization

Stimulatory role of nectin‐4 and p95‐ErbB2 in multilayered T47D cell proliferation

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