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Involvement of kallikrein-related peptidase 6 in epithelial to mesenchymal transition induced by ΔNp63 downregulation in oral squamous cell carcinoma through activation of protease activated receptors

ABSTRACT: Recent studies showed epithelial-mesenchymal transition (EMT) is involved in cancer progression. Though we revealed that downregulation of ΔNp63 in oral squamous cell carcinoma (OSCC) induces EMT, the detailed molecular mechanisms remain to be elucidated. DNA microarray analyses were thus performed by using OSCC cell line overexpressing ΔNp63 to examine the genes associated with EMT. The results revealed that kallikrein related peptidase 6 (KLK6) was most upregulated in the OSCC cells overexpressing ΔNp63.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90064 | GEO | 2018/04/01

REPOSITORIES: GEO

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Project description:Epithelial-to-mesenchymal transition (EMT) is a dynamic process and critically contributes to treatment resistance, cancer cell dissemination and metastasis. Main objective of this study was to investigate the functional interaction between Kallikrein-related peptidase 6 (KLK6) and aldehyde dehydrogenase 1A (ALDH1A)-related retinoic acid (RA) signaling as recent studies reported their impact on molecular features resembling EMT in several malignancies, including head and neck squamous cell carcinoma (HNSCC). In HNSCC cell lines, we demonstrate that KLK6 is not only a downstream target of ALDH1A-related RA signaling, but also acts as an upstream regulator of ALDH1A3 expression. KLK6 and ALDH1A3 co-expression was confirmed in a mouse xenograft model and two independent HNSCC cohorts (HIPO-HNC and TCGA-HNC). KLK6 and ALDH1A3 co-expressed genes in HNSCC, which are also differentially expression in HNSCC cells with silenced KLK6 expression unraveled several subgroups of HNSCC patients with distinct histopathological and clinical features. In summary, our study highlights a new functional circuit with KLK6 and ALDH1A3 as key nodes and unraveled a gene expression signature, which predicts unfavorable prognosis in human papilloma virus (HPV)-negative HNSCC.

2021-11-01 | GSE122448 | GEO

KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Project description:Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from psoriasis patients. Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.

2020-03-25 | GSE144312 | GEO

Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

Project description:Kallikrein-related peptidase 7 (KLK7) is a serine peptidase that is over-produced in the most lethal form of ovarian cancer, called high grade serous ovarian cancer (HGSOC). To determine its underlying molecular mechanism of action, a comprehensive analysis of KLK7 degradome in the SKOV-3 cell-secreted proteins was performed using two complementary proteomic approaches, quantitative PROtein Topography and Migration Analysis Platform (qPROTOMAP) and Terminal Amine Isotopic Labelling of Substrates (TAILS).

2019-02-15 | PXD003752 | Pride

Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

Project description:Kallikrein-related peptidase 7 (KLK7) is a serine peptidase that is over-produced in the most lethal form of ovarian cancer, called high grade serous ovarian cancer (HGSOC). To determine its underlying molecular mechanism of action, a comprehensive analysis of KLK7 degradome in the OVMZ-6 cell-secreted proteins was performed using two complementary proteomic approaches, quantitative PROtein Topography and Migration Analysis Platform (qPROTOMAP) and Terminal Amine Isotopic Labelling of Substrates (TAILS).

2019-02-15 | PXD004591 | Pride

Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

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Differences of miRNA expression associated with ΔNp63β overexpressing OSCC cell line SQUU-B

Project description:Recent reports have revealed that EMT is involved in cancer invasion and progression including oral squamous cell carcinoma (OSCC). Previously, we have also studied on the association of p63 gene, a homolog of the p53 tumor suppressor gene, with EMT in OSCC cells. Furthermore, we also demonstrated that down-regulation of ΔNp63 accompanied with EMT and that re-expression of ΔNp63β by stable cDNA transfection in OSCC cell lines reverted the EMT phenotype. However, the detail mechanisms of ΔNp63β-mediated EMT remain to be unclear. Recent studies have shown that several microRNAs (miRNAs) are also involved in EMT process of human cancer by targeting EMT-related transcription factors. We thus sought to identify responsible miRNA associated with ΔNp63β-mediated EMT using miRNA microarray analyses.

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Validation and application of a novel KLK6 activity based probe (IMP2352)

Project description:Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABP) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M-1 s-1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a new toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases.

2023-03-10 | PXD035111 | Pride

Kallikrein-mediated cytokeratin 10 degradation is required for VZV propagation in skin

Project description:Varicella Zoster Virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening particularly in the immunocompromised. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and anti-viral drugs. In VZV- infected skin, Kallikrein 6 (KLK6), and the ubiquitin-ligase MDM2 are up-regulated concomitant with Keratin 10 (K10) down-regulation. MDM2 binds to K10 targeting it for degradation via the ubiquitin-proteasome pathway. Preventing K10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. K10 knockdown induced expression of the nuclear receptor subfamily 4, group A, member 1 (NR4A1) and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels and increased LAMP2 expression. We therefore describe a novel drug-able pathway whereby MDM2 ubiquitinates and degrades K10 increasing NR4A1 expression allowing VZV replication and propagation.

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ΔNp63 controls stemness and inflammation in the adult epidermis

Project description:The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is barely investigated. Here we show that acute genetic ablation of ΔNp63, the main p63 isoform, in the adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in ΔNp63-ablated keratinocytes. Intriguingly, ΔNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This was not associated with active cell death mechanisms, but rather with reduced stemness and self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, was largely impaired in the ablated skin. We found that the Wnt signaling pathway (Wnt5a, Wnt10a, Fzd6, Fzd10) and Col17a1 are the likely ΔNp63 effectors responsible for keratinocyte proliferation and stemness, while AP1 factors are responsible for excessive differentiation, and Il-1a, Il-18, Il-24 and Il-36γ for the suppression of inflammation. These data implicate ΔNp63 as a critical node that coordinates balanced epidermal homeostasis and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.

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