Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer

Abstract

Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKCα. The depletion of PHF8 or PKCα greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKCα expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKCα-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKCα, and PTEN showed a positive correlation between PHF8 and PKCα but negative correlations between PHF8 and PTEN and between PKCα and PTEN. Moreover, high PHF8-PKCα expression was significantly correlated with worse prognosis. Together, our results suggest that the PKCα-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.

The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

“…Mutations in PHF8 are associated with X-linked mental retardation and cleft lip/cleft palate (31), and the modulation of histone methylation by PHF8 plays a critical role in neuronal differentiation and brain and craniofacial development (11). PHF8 overexpression in malignant cells has been reported in several cancers, including acute lymphoblastic leukemia (32), breast cancer (33), colorectal cancer (34), gastric cancer (35,36), prostate cancer (37)(38)(39)(40), and hepatocellular carcinoma (41). However, PHF8 occupancy and its downstream transcriptional programs in those tumor types have not been elucidated.…”

Identification of the shared gene signatures and pathways between polycystic ovary syndrome and endometrial cancer: An omics data based combined approach

“…Analysis of the network showed that KLF9, PHF8, KDM5B and SAP30 were significantly correlated TFs with hub genes. They have all been shown to take part in tumorigenesis [ 39 – 42 ]. Moreover, previous studies have suggested that KLF9 is a tumor suppressor involved in development of EC [ 43 ].…”

lncRNAs Functioned as ceRNA to Sponge miR-15a-5p Affects the Prognosis of Pancreatic Adenocarcinoma and Correlates With Tumor Immune Infiltration

“…With advances in high-throughput sequencing technology, more biomarkers can be discovered to determine prognosis and improve treatment strategies ( Zhang et al, 2018 ; Ping et al, 2020 ; Qiu et al, 2020 ). Non-coding RNAs (ncRNAs) have an important role in the occurrence and development of cancer and are promising biomarkers and therapeutic targets ( Cai et al, 2020 ; Mu et al, 2020 ; Tseng et al, 2020 ). lncRNAs are broadly defined as non-coding RNA with a length greater than 200 nucleotides, which previously were thought to have limited protein-coding ability ( Mi et al, 2020 ).…”