K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

Canales, Jimena; Cruz, Pablo; Díaz, Nicolás Masquiarán; Riquelme, D.; Leiva-Salcedo, Elías; Cerda, Oscar

doi:10.3390/cells9102273

Cited by 11 publications

(13 citation statements)

References 77 publications

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“…Focal adhesions analyses were performed as described [ 55 ]. Fifty thousand cells per well were seeded in 24-well plates on glass coverslips coated with fibronectin.…”

Section: Methodsmentioning

confidence: 99%

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

López-Moncada

Torres

Lavanderos

et al. 2022

IJMS

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Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway.

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“…Focal adhesions analyses were performed as described [ 55 ]. Fifty thousand cells per well were seeded in 24-well plates on glass coverslips coated with fibronectin.…”

Section: Methodsmentioning

confidence: 99%

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

López-Moncada

Torres

Lavanderos

et al. 2022

IJMS

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“…KCTD5 is a putative adaptor for Cullin3-E3 ubiquitin ligase and could contribute to TRPM4 turnover via ubiquitinoylation. In addition, KCTD5 regulates migration by altering Ca 2+ signaling, possibly via TRPM4 or other ion channels and Rac1 activity [ 122 , 123 ]. Moreover, in a gene set enrichment analysis of three breast cancer gene expression profiling data sets, TRPM4 expression was shown to be associated with EMT gene sets and estrogen response gene sets [ 40 ].…”

Section: Functional Role Of Trpm4 In Different Types Of Cancermentioning

confidence: 99%

TRPM4 in Cancer—A New Potential Drug Target

2021

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Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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“…Moreover, the present findings suggest that the monitoring and the modulation of KCTD15 expression and activity can be effectively used for both diagnostic/prognostic and therapeutic scopes with a specific focus on HER2+ BC. Finally, considering the involvement of other KCTD proteins in BC [10,[49][50][51], investigations aimed at elucidating precise molec-ular mechanisms involving KCTD15 are in progress. The ability of this protein to play roles in diversified contexts suggests that it likely performs a basic biochemical activity.…”

Section: Discussionmentioning

confidence: 99%

KCTD15 Is Overexpressed in her2+ Positive Breast Cancer Patients and Its Silencing Attenuates Proliferation in SKBR3 CELL LINE

Coppola¹,

Baselice²,

Messina³

et al. 2022

Diagnostics

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Studies carried out in the last decade have demonstrated that the members of the KCTD protein family play active roles in carcinogenesis. Very recently, it has been reported that KCTD15, a protein typically associated with other physio-pathological processes, is involved in medulloblastoma and leukemia. Starting with some preliminary indications that emerged from the analysis of online databases that suggested a possible overexpression of KCTD15 in breast cancer, in this study, we evaluated the expression levels of the protein in breast cancer cell lines and in patients and the effects of its silencing in the HER2+ cell model. The analysis of the KCTD15 levels indicates a significant overexpression of the protein in Luminal A and Luminal B breast cancer patients as well as in the related cell lines. The greatest level of over-expression of the protein was found in HER2+ patients and in the related SKBR3 cell line model system. The effects of KCTD15 silencing in terms of cell proliferation, cell cycle, and sensitivity to doxorubicin were evaluated in the SKBR3 cell line. Notably, the KCTD15 silencing in SKBR3 cells by CRISPR/CAS9 technology significantly attenuates their proliferation and cell cycle progression. Finally, we demonstrated that KCT15 silencing also sensitized SKBR3 cells to the cytotoxic agent doxorubicin, suggesting a possible role of the protein in anti HER2+ therapeutic strategies. Our results highlight a new possible player in HER2 breast cancer carcinogenesis, paving the way for its use in breast cancer diagnosis and therapy.

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K+ Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca2+ Signaling and Rac1 Activity

Cited by 11 publications

References 77 publications

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

TRPM4 in Cancer—A New Potential Drug Target

KCTD15 Is Overexpressed in her2+ Positive Breast Cancer Patients and Its Silencing Attenuates Proliferation in SKBR3 CELL LINE

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