Systemic Profiling of KDM5 Subfamily Signature in Non-Small-Cell Lung Cancer

Abstract

Background: Despite improvements in diagnosis and treatment, lung cancer is one of the most lethal human diseases, with a dismal 5-year relative survival rate of only 5% for patients diagnosed with advanced metastatic disease. Accumulating evidence supports that epigenetic aberration of histone demethylase-KDM5 subfamily is linked to human pancancer. However, the detailed functions of KDM5 proteins in lung cancer, especially in nonsmall-cell lung cancer (NSCLC), remain poorly understand. Methods: UALCAN, GEPIA, Kaplan-Meier plotter, cBioPortal, TIMER, TISIDB, and STRING databases were utilized in this investigation. Results: We detected varying degrees of gene mutations of KDM5 subfamily members and found that KDM5B/C were remarkably overexpressed in LUAD and LUSC compared to normal tissues. Different from KDM5D, positive relationship was shown between overall survival and mRNA expression of KDM5A/B/C in lung cancer. We determined that KDM5A/B/C expression levels were positively correlated with CD4+ T cells infiltration, especially immunological markers of Tregs and Th17 cells. Moreover, LUAD and LUSC were separately rich in inflammatory and wound healing subtypes after immunogenomics analyzing with respect to KDM5 subfamily overexpression. And with their 120 co-expressed genes, we revealed that nucleocytoplasmic transport and cellular protein localization-related genes were closely connected to KDM5 subfamily alterations, next to chromatin remodeling genes. Conclusion:We formulated the immune-infiltrating and prognostic value of KDM5 subfamily and highlighted its promising role in immune-inflammatory interaction with tumour microenvironment in NSCLC.

KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas

“…Prognostic analysis revealed that KDM5 family members were strongly associated with relevant clinicopathological factors and prognosis. A previous study has confirmed that alterations in the KDM5 gene family may affect the prognosis of patients with non-small cell lung cancer 26 . There is increasing evidence suggesting that deregulation of KDM5 family may have important phenotypic consequences in various types of cancer, including the role of KDM5 family demethylases in the emergence of drug tolerance 27 .…”

A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression

“…KDM5B has an ambivalent role in oncogenesis, behaving as an oncogene in some cancer cell lines and as a tumor suppressor in others [ 12 , 36 ]. This could partly depend on the pattern of the isoforms expressed in different cell lines.…”

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

“…It is an attractive target in cancer therapy. Several prospective raw letter analyses have shown that KDM5 is closely associated with regulaing immune infiltration and expressing immune-related molecules, and is considered a prospective candidate for epigenetic anti-tumor therapy ( 117 – 119 ). In clinical treatment, some patients have low tumor cell PD-L1 abundance, so they cannot respond well to ICB.…”