SMAR1 and p53‐regulated lncRNA RP11‐431M3.1 enhances HIF1A translation via miR‐138 in colorectal cancer cells under oxidative stress

• Published in: The FEBS journal 2024-11, Vol.291 (21), p.4696-4713
• Main Authors: Bose, Ganesh Suraj, Jindal, Shruti, Landage, Kiran Gautam, Jindal, Aarzoo, Mahale, Monali Prakash, Kulkarni, Abhijeet P., Mittal, Smriti
• Format: Article
• Language: English
• Subjects: Apoptosis; Cell Cycle Proteins; Cell migration; Cell proliferation; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Data mining; diagnostic or prognostic; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genes; HCT116 Cells; Humans; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; lncRNA; Metastases; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Non-coding RNA; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; oncogenic or tumor suppressor; Oxidative Stress; p53 Protein; Pathogenesis; Reactive oxygen species; Regulatory mechanisms (biology); RNA, Long Noncoding - genetics; ROS; Survival; Transcription factors; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17253

Eukaryotic cells respond to stress by altering coding and non‐coding gene expression programs. Alongside many approaches and regulatory mechanisms, long non‐coding RNAs (lncRNA) are finding a significant place in gene regulation, suggesting an involvement in various cellular processes and pathophysiology. LncRNAs are regulated by many transcription factors, including SMAR1 and p53, which are tumor suppressor genes. SMAR1 inhibits cancer cell metastasis and invasion and is also known to inhibit apoptosis during low‐dose stress in coordination with p53. Data mining analysis suggested that these tumor suppressor genes might coregulate the lncRNA RP11‐431M3.1 in colon cancer cells. Importantly, RP11‐431M3.1 expression was found to be negatively correlated with patient survival rates in a number of cancers. Oxidative stress occurs when an imbalance in the body is caused by reactive oxygen species (ROS). This imbalance is known to be important in the development/pathogenesis of colon cancer. We are researching the role and control of this lncRNA in HCT116 cells under conditions of oxidative stress. We observed a dose‐dependent differential expression of lncRNA upon H2O2 treatment and found that p53 and SMAR1 bind differentially to the promoter in response to the dose of stress inducer used. RP11‐431M3.1 was observed to sponge miR‐138 which has an important target gene, hypoxia‐inducible factor (HIF1A). miR‐138 was observed to bind differentially to RP11‐431M3.1 and HIF1A RNA depending on the dose of oxidative stress. Furthermore, the knockdown of RP11‐431M3.1 decreased the migration and proliferation of colon cancer cells. Our results suggest a previously undescribed regulatory mechanism through which RP11‐431M3.1 is transcriptionally regulated by SMAR1 and p53, target HIF1A through miR‐138, and highlight its potential as a therapeutic and diagnostic marker for cancer. Here, we explored the differential regulation of the long non‐coding RNA (lncRNA) RP11‐431M3.1 by p53 and SMAR1 under oxidative stress conditions in colon cancer. We found that RP11‐431M3.1 is transcriptionally regulated by SMAR1 and p53 and targets HIF1A through miR‐138. Importantly, knockdown of RP11‐431M3.1 decreased the migration and proliferation of colon cancer cells, suggesting its potential as a therapeutic and diagnostic marker.