Abstract
Suppressor with morphogenetic effect on genitalia family member (SMG1) belongs to a family of phosphoinositide 3-kinase-related kinases and is the main kinase involved in nonsense-mediated mRNA decay. Recently, SMG1 was suggested as a novel potential tumor suppressor gene, particularly in hypoxic tumors. To investigate the function of SMG1 in acute myeloid leukemia (AML), we performed methylation-specific polymerase chain reaction and found that SMG1 was hypermethylated in the promoter region. SMG1 hypermethylation was found in 66% (33/50) of AML samples compared with none (0/14) of the normal controls. SMG1 mRNA was down-regulated in AML patients with hypermethylation status whereas it was readily expressed in patients without methylation. Moreover, treatment of AML cells with demethylating agent 5-aza-2'-deoxycytidine (decitabine) inhibited AML cell growth and induced apoptosis by reversing SMG1 methylation status and restoring SMG1 expression. On the other hand, knockdown of SMG1 by RNA interference inhibited apoptosis. We also found that mTOR expression level was negatively correlated to SMG1 expression in AML patients which indicated that SMG1 and mTOR maybe act antagonistically to regulate AML cell growth. In conclusion, our results indicate that SMG1 acts as a potential tumor suppressor with epigenetic regulation in AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disorder of hematopoiesis characterized by the uncontrolled proliferation and accumulation of immature and dysfunctional hematopoietic progenitors.Cytotoxic chemotherapy has been widely used as the main approach for AML treatment.Recent studies have proved that, the successive accumulation of genetic alterations in oncogenes and tumor suppressor genes, and the epigenetic alterations contribute to carcinogenesis [1]
We found that SMG1 expression level was negatively correlated with its methylation status and Mammalian target of rapamycin (mTOR) expression level respectively which indicated that SMG1 and mTOR may act antagonistically to regulate AML cell growth
SMG1 Was Down-Regulated in Acute Myeloid Leukemia (AML) Patient Samples
Summary
Acute myeloid leukemia (AML) is a clonal disorder of hematopoiesis characterized by the uncontrolled proliferation and accumulation of immature and dysfunctional hematopoietic progenitors. Alterations of the methylation status in oncogenes and tumor suppressor genes, which could affect the mRNAs and proteins expression levels, result in uncontrolled cell growth . Mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation and is essential for the process of protein synthesis, which is consistent with that many human genetic defects and tumors associating with mTOR up-regulation manifest as uncontrolled cell growth [7]. We found that SMG1 expression level was negatively correlated with its methylation status and mTOR expression level respectively which indicated that SMG1 and mTOR may act antagonistically to regulate AML cell growth. Our results indicate that SMG1 acts as a potential tumor suppressor with epigenetic regulation and highlights a new approach for the demethylating treatment of DAC in AML
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