Histone demethylase KDM4A plays an oncogenic role in nasopharyngeal carcinoma by promoting cell migration and invasion

Abstract

Compelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) and the mechanistic target of rapamycin (mTOR) signaling pathway in nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1α/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

“…Increased expression of KDM4A has been documented in various types of cancers [ 26 , 43 ], and KDM4A serves as an oncogene in CC [ 32 ]. Our result showed the KDM4A expression was gradually increased in squamous cell carcinoma of the cervix and in SiHa and Hela cells treated with hypoxia for 0.5-12 h with the prolongation of hypoxia time.…”

“…Histone H3 lysine 9 trimethylation (H3K9me3) is a pivotal epigenetic mechanism suppressing gene expressions [ 25 ]. Once KDM4A is depleted or deactivated, H3K9me3 accumulates at the HIF1 α site, leading to HIF1 α downregulation and stability decline [ 26 ]. Loss of SUV39H1 manipulates the H3K9me3 status of the DPP4 gene promoter to raise its expression, thus contributing to ferroptosis [ 27 ].…”

SUMO Modification of Histone Demethylase KDM4A in Kaposi’s Sarcoma-Associated Herpesvirus-Induced Primary Effusion Lymphoma

“…Since SUMOylation is required for chromatin binding and consequently demethylase activity of KDM4A, rescuing overexpression of KDM4A-K471R mimics the knockdown phenotype ( 25 ). In addition to the viral effect, KDM4A has also been recognized as an oncogene that is highly expressed in various human cancers ( 40 , 41 ) and inhibits apoptosis ( 42 – 44 ). Therefore, we hypothesize that induction of KSHV reactivation in KDM4A knockdown BCBL-1 cells or cells expressing a SUMO-deficient mutant of KDM4A may lead to incomplete viral lytic replication and cell death.…”

Clustering of Chromatin Remodeling Enzymes Predicts Prognosis and Clinical Benefit of Therapeutic Strategy in Pancreatic Cancer

“…Loss of SUV420H2 facilitates upregulation of LINC01510, which promotes the transcription of the oncogene MET and EGFR inhibitor resistance in lung cancer 38 . KDM4A serves as a poor prognostic marker and plays an oncogenic role in oral squamous cell carcinoma and nasopharyngeal cancer 39 , 40 . In contrast to SUV39H1, SUV39H2 expression is elevated and might be a potential oncogene that mediates tumorigenesis and metastasis in lung adenocarcinoma 41 .…”