HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3

Abstract

Background Histone deacetylases (HDACs) have been shown to be involved in tumorigenesis, but their precise role and molecular mechanisms in gastric cancer (GC) have not yet been fully elucidated. Methods Bioinformatics screening analysis, qRT-PCR, and immunohistochemistry (IHC) were used to identify the expression of HDAC4 in GC. In vitro and in vivo functional assays illustrated the biological function of HDAC4. RNA-seq, GSEA pathway analysis, and western blot revealed that HDAC4 activated p38 MAPK signalling. Immunofluorescence, western blot, and IHC verified the effect of HDAC4 on autophagy. ChIP and dual-luciferase reporter assays demonstrated that the transcriptional regulation mechanism of HDAC4 and ATG4B. Results HDAC4 is upregulated in GC and correlates with poor prognosis. In vitro and in vivo assays showed that HDAC4 contributes to the malignant phenotype of GC cells. HDAC4 inhibited the MEF2A-driven transcription of ATG4B and prevented MEKK3 from p62-dependent autophagic degradation, thus activating p38 MAPK signalling. Reciprocally, the downstream transcription factor USF1 enhanced HDAC4 expression by regulating HDAC4 promoter activity, forming a positive feedback loop and continuously stimulating HDAC4 expression and p38 MAPK signalling activation. Conclusion HDAC4 plays an oncogenic role in GC, and HDAC4-based targeted therapy would represent a novel strategy for GC treatment.

HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications

“…HDAC4 has been reported to both suppress and stimulate autophagy ( Kang et al, 2014 ; Yue et al, 2015 ; Pigna et al, 2018 ; Yang et al, 2018 ). The involvement of HDAC4 in regulating autophagy may also be part of feedforward circuits that maintain malignancy ( Zang et al, 2022 ). The relationships between HDAC4 and autophagy are complex and require further investigation.…”

Histone Deacetylase Functions in Gastric Cancer: Therapeutic Target?

“…HDAC4: The good aspect about HDAC4 is that all expression studies agreed that HDAC4 displays an increased expression in gastric tumors [ 54 , 55 , 56 , 57 , 58 ]. Unfortunately, most studies were done only on small cohorts of patients.…”

“…Its expression tends also to be higher in the diffuse-type GC of Lauren’s classification, often associated with the GS subgroup [ 57 ]. Additionally, high HDAC4 expression is correlated with an advanced invasion of the gastric mucus, LNM, and TNM stage, and is associated with a shorter overall survival and DFS in GC patients [ 58 ]. Interestingly, HDAC4 seems to be a resistance factor in GC, because when it is overexpressed or inhibited by specific siRNAs, GC cells become more or less resistant to cisplatin, respectively [ 57 ].…”

“…Importantly, and underlining the role of HDAC4 as resistance and pro-tumoral factor, is that when going deeper into the analysis of TCGA data on GC, Spaety and co-workers found that patients with a mutated HDAC4 have an overall better survival than patients with a wild type HDAC4 [ 57 ]. Mechanistically, silencing of HDAC4 inhibits cell proliferation, migration, and invasion via the HDAC4/ATG4B/MEKK3/p38 pathway [ 58 ] but favors cell cycle arrest and apoptosis, characterized by cleavage of caspase-3 and induction of proapoptotic genes, such as BIK or p21 , in part via a p53-dependent mechanism [ 55 , 57 ]. In addition, lncRNAs and miRNAs have been shown to impact the HDAC4 expression in GC.…”

Prognostic Value and Potential Regulatory Mechanism of H19 in Stomach Adenocarcinoma

“…For advanced STAD, cytotoxic chemotherapy remains the main first-line treatment strategy [7,8]. Although the addition of targeted therapy in later-line treatment was proven to be beneficial when compared with chemotherapy alone [9][10][11], therapeutic targets for advanced gastric cancer are exceedingly rare. Therefore, the discovery of new biomarkers is likely to brew new precision treatments for treatment of STAD in the future [12,13], and investigation into the mechanisms underlying STAD may become the key to finding novel approaches for prognosis improvement and drug development.…”