LncRNA ZNF295-AS1 modulates nasopharyngeal carcinoma progression via the miR-762/HDAC6 axis-mediated autophagy

Abstract

Long non-coding RNAs (lncRNAs) and autophagy play pivotal roles in the pathogenesis of nasopharyngeal carcinoma (NPC), yet the mechanisms underlying lncRNA-mediated autophagy regulation in NPC remain largely unknown. This study aimed to identify critical autophagy-related lncRNAs in NPC and to elucidate the functional role and molecular mechanisms of ZNF295-AS1 in modulating autophagy and tumor progression. We systematically screened for autophagy-associated lncRNAs by analyzing the NPC gene expression dataset GSE12452 from the GEO database, employing integrated differential expression analysis coupled with machine learning techniques. Subsequently, we constructed a co-expression network of lncRNAs and autophagy-related genes using bioinformatics tools. The expression and clinical implications of ZNF295-AS1 and its target HDAC6 were validated through a combination of RNA in situ hybridization, quantitative RT-PCR, immunohistochemistry, and functional assays conducted in NPC cell lines and xenograft models. We assessed autophagic flux using fluorescence dual-reporter assays, Western blotting, and transmission electron microscopy, while investigating the role of miR-762 in regulatory mechanisms via molecular interaction assays. Our results highlight that ZNF295-AS1 is a novel autophagy-associated lncRNA that is positively correlated with HDAC6 and is downregulated in NPC tissues, with low expression levels being associated with poor prognosis. Overexpression of ZNF295-AS1 was found to inhibit NPC cell proliferation, migration, and invasion, while disrupting autophagic flux and leading to an accumulation of p62 and LC3B-II; these effects were reversed by HDAC6 knockdown and miR-762 overexpression. Mechanistically, ZNF295-AS1 functions as a competing endogenous RNA, sponging miR-762 and thus relieving the repression of HDAC6, ultimately influencing autophagy and tumor progression. In conclusion, ZNF295-AS1 is implicated in the regulation of autophagy and malignancy in NPC through the miR-762/HDAC6 axis, suggesting its potential as a novel diagnostic and therapeutic target in NPC management.