ABSTRACT
Cervical cancer, a leading global cause of female mortality, exhibits diverse molecular aberrations influencing gene expression and signaling pathways. Epigenetic factors, including histone deacetylases (HDACs) such as HDAC8 and HDAC6, along with microRNAs (miRNAs), play pivotal roles in cervical cancer progression. Recent investigations have unveiled miRNAs as potential regulators of HDACs, offering a promising therapeutic avenue. This study employed in-silico miRNA prediction, qRT-PCR co-expression studies, and Dual-Luciferase reporter assays to identify miRNAs governing HDAC8 and HDAC6 in HeLa, cervical cancer cells. Results pinpointed miR-497-3p and miR-324-3p as novel negative regulators of HDAC8 and HDAC6, respectively. Functional assays demonstrated that miR-497-3p overexpression in HeLa cells suppressed HDAC8, leading to increased acetylation of downstream targets p53 and α-tubulin. Similarly, miR-324-3p overexpression inhibited HDAC6 mRNA and protein expression, enhancing acetylation of Hsp90 and α-tubulin. Notably, inhibiting HDAC8 via miRNA overexpression correlated with reduced cell viability, diminished epithelial-to-mesenchymal transition (EMT), and increased microtubule bundle formation in HeLa cells. In conclusion, miR-497-3p and miR-324-3p emerge as novel negative regulators of HDAC8 and HDAC6, respectively, with potential therapeutic implications. Elevated expression of these miRNAs in cervical cancer cells holds promise for inhibiting metastasis, offering a targeted approach for intervention in cervical malignancy.
ABSTRACT
Cancer metastasis and drug resistance are two major obstacles in the treatment of cancer and therefore, the leading cause of cancer-associated mortalities worldwide. Hence, an in-depth understanding of these processes and identification of the underlying key players could help design a better therapeutic regimen to treat cancer. Earlier thought to be merely transcriptional junk and having passive or secondary function, recent advances in the genomic research have unravelled that long noncoding RNAs (lncRNAs) play pivotal roles in diverse physiological as well as pathological processes including cancer metastasis and drug resistance. LncRNAs can regulate various steps of the complex metastatic cascade such as epithelial-mesenchymal transition (EMT), invasion, migration and metastatic colonization, and also affect the sensitivity of cancer cells to various chemotherapeutic drugs. A substantial body of literature for more than a decade of research evince that lncRNAs can regulate gene expression at different levels such as epigenetic, transcriptional, posttranscriptional, translational and posttranslational levels, depending on their subcellular localization and through their ability to interact with DNA, RNA and proteins. In this review, we mainly focus on how lncRNAs affect cancer metastasis by modulating expression of key metastasis-associated genes at various levels of gene regulation. We also discuss how lncRNAs confer cancer cells either sensitivity or resistance to various chemo-therapeutic drugs via different mechanisms. Finally, we highlight the immense potential of lncRNAs as prognostic and diagnostic biomarkers as well as therapeutic targets in cancer.