Recent advances on regulatory roles of HuD and promoter hypermethylation for miR-204 in lung cancer development

Abstract

Lung cancer, responsible for the highest number of cancer-related deaths globally, comprises small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), two subtypes with fundamentally different molecular mechanisms and disease trajectories. The tumor-suppressive microRNA miR-204 is frequently inactivated in lung cancer and plays a central role in driving progression and metastasis. Recent work has uncovered striking differences in how miR-204 is downregulated in each subtype. In SCLC, the RNA-binding protein HuD stabilizes oncogenic long non-coding RNAs (lncRNAs) and PFN2 mRNA, leading to reduced miR-204-5p levels and increased cell migration. By contrast, in NSCLC, epigenetic silencing via miR-204 promoter hypermethylation decreases its expression, derepressing NUAK1 , activating mTOR signaling, and promoting tumor progression. Despite operating through distinct pathways, both mechanisms converge on miR-204 loss to foster malignancy. This minireview summarizes these recent insights into the HuD-lncRNA axis and epigenetic regulation of miR-204, evaluates their clinical implications, and discusses emerging multimodal approaches that target the miR-204 network for more effective precision therapy in lung cancer.