DIRAS family GTPase 1 (DIRAS1) has been reported as a potential tumor suppressor in other human cancer. However, its expression pattern and role in cervical cancer remain unknown. Knockdown of DIRAS1 significantly promoted the proliferation, growth, migration, and invasion of C33A and SiHa cells cultured in vitro. Overexpression of DIRAS1 significantly inhibited the viability and motility of C33A and SiHa cells. Compared with normal cervical tissues, DIRAS1 mRNA levels were significantly lower in cervical cancer tissues. DIRAS1 protein expression was also significantly reduced in cervical cancer tissues compared with para-cancerous tissues. In addition, DIRAS1 expression level in tumor tissues was significantly negatively correlated with the pathological grades of cervical cancer patients. DNA methylation inhibitor (5-Azacytidine) and histone deacetylation inhibitor (SAHA) resulted in a significant increase in DIRAS1 mRNA levels in C33A and SiHa cells, but did not affect DIRAS1 protein levels. FTO inhibitor (FB23-2) significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels. Moreover, the down-regulation of METTL3 and METTL14 expression significantly inhibited DIRAS1 protein expression, whereas the down-regulation of FTO and ALKBH5 expression significantly increased DIRAS1 protein expression. In conclusion, DIRAS1 exerts a significant anti-oncogenic function and its expression is significantly downregulated in cervical cancer cells. The m6A modification may be a key mechanism to regulate DIRAS1 mRNA stability and protein translation efficiency in cervical cancer.

01 Dec 2024·Functional & Integrative Genomics

Regulation of m6A (N6-Methyladenosine) methylation modifiers in solid cancers

Review

Author: Singh, Sakshi ; Gupta, Sudha ; Sachan, Manisha ; Abhishek, Rajul

Solid cancers constitute a tremendous burden on global healthcare, requiring a deeper understanding of the molecular mechanisms underlying cancer development and progression. Epigenetic changes, notably N⁶-methyladenosine (m⁶A) RNA methylation, have emerged as important contributors to the biology of solid tumors in recent years. This epigenetic mark dynamically affects gene expression at the post-transcriptional level and modulates a variety of cellular processes, making it a focus of research in the context of solid tumors. m⁶A modification patterns are dysregulated in a variety of solid cancers, including ovarian, breast, lung, colorectal, pancreatic, and others. This dysregulated m⁶A landscape has been shown to induce significant changes in the expression of oncogenes, tumor suppressors, and genes involved in cancer stem cells, metastasis, and treatment resistance. In solid tumors, the interaction of m⁶A "writers" (e.g., METTL3, METTL14, and others), "erasers" (e.g., ALKBH5, FTO), and "readers" (e.g., members of YTHDF proteins and others) delicately changes the m⁶A methylome. Targeting m⁶A regulators as a potential therapeutic method to control gene expression and prevent tumor development seems a novel strategy. To enhance treatment results, advances in this area of research have led to the development of targeted treatments aiming at restoring or altering m⁶A alteration patterns in solid tumors.

01 Dec 2024·Molecular Biology Reports

Curcumin reduces myocardial ischemia-reperfusion injury, by increasing endogenous H2S levels and further modulating m6A

Article

Author: Wang, Xin ; Dong, Lingling ; Wang, Qinwen ; Cui, Jiankun

BACKGROUNDOur previous research shows that Curcumin (CUR) attenuates myocardial ischemia-reperfusion injury (MIRI) by reducing intracellular total RNA m⁶A levels. However, the mechanism remains unknown.METHODSFor ischemia-reperfusion (IR), H9c2 cells were cultured for 6 h in serum-free low-glycemic (1 g/L) medium and a gas environment without oxygen, and then cultured for 6 h in high-glycemic (4.5 g/L) medium supplemented with 10% FBS and a 21% oxygen environment. The effects of different concentrations of CUR (5, 10, and 20 µM) treatments on signaling molecules in conventionally cultured and IR-treated H9c2 cells were examined.RESULTSCUR treatment significantly up-regulated the H₂S levels, and the mRNA and protein expression of cystathionine γ-lyase (CSE), and down-regulated the mRNAs and proteins levels of thiosulfate sulfurtransferase (TST) and ethylmalonic encephalopathy 1 (ETHE1) in H9c2 cells conventionally cultured and subjected to IR. Exogenous H₂S supply (NaHS and GYY4137) significantly reduced intracellular total RNA m⁶A levels, and the expression of RNA m⁶A "writers" METTL3 and METTL14, and increased the expression of RNA m⁶A "eraser" FTO in H9c2 cells conventionally cultured and subjected to IR. CSE knockdown counteracted the inhibitory effect of CUR treatment on ROS production, promotion on cell viability, and inhibition on apoptosis of H9c2 cells subjected to IR.CONCLUSIONCUR attenuates MIRI by regulating the expression of H₂S level-regulating enzymes and increasing the endogenous H₂S levels. Increased H₂S levels could regulate the m⁶A-related proteins expression and intracellular total RNA m⁶A levels.

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