Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance

Abstract

microRNA-33a (miR-33a) belongs to the miR-33 family that is implicated in the progression of various types of cancers. Aberrant expression of miR-33a has been detected in several human cancers, and has been shown to regulate the migration and invasion as well as proliferation and apoptosis of tumor cells. However, the clinical significance and precise mechanisms underlying the dysfunction of miR-33a in glioma have not been well investigated in previous studies. In this study, overexpression of miR-33a was observed in clinical glioma specimens and cell lines. Clinicopathological detection revealed that miR-33a highly expressing patients showed large tumor sized and advanced World Health Organization (WHO) grade as well as reduced overall survival. Furthermore, the results of in vitro experiments confirmed that loss of miR-33a resulted in reduced proliferation and enhanced apoptosis in U251 cells, while miR-33a restoration showed opposite effects in U87 cells. Further studies indicated that miR-33a knockdown restrained tumor growth of glioma in vivo. miR-33a negatively regulated the expression of sirtuin 6 (SIRT6) at both mRNA and protein levels via targeting the 3'UTR of SIRT6 mRNA. SIRT6 was underexpressed and inversely correlated with miR-33a expression in the glioma tissues. Mechanistically, SIRT6 overexpression increased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) while it reduced cell survival under H2O2 treatment. In addition, SIRT6 restoration led to apoptosis with alterative expression of Bax, Bcl-2, cleaved caspase-8, and inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in glioma. Thus, our studies demonstrated that the deregulation of miR-33a may promote tumor development in human glioma by regulating the expression of its target gene, SIRT6.

<p>Knockdown of circ-TTBK2 Inhibits Glioma Progression by Regulating miR-1283 and CHD1</p>

“…Besides, the subcutaneous xenograft model using U251 cells is helpful for understanding the potential mechanism of glioma in vivo. [27][28][29] Here we using the xenograft model further confirmed the anti-tumor role of circ-TTBK2 inhibition in glioma via regulating the miR-1283/CHD1 axis in vivo.…”

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

“…The increased ATP level upon SIRT6 activation states for increased NADH oxidation and nicely correlates with increased ROS production. Moreover, it is reported that overexpression of SIRT6 results in increased ROS production and that a specific miR-33a by suppressing SIRT6 induced tumor growth through oxidative stress resistance 46 . Work is in progress in our laboratory in order to fill this gap.…”

Role of microRNA‑33a in malignant cells (Review)

“…Downregulation of SIRT6 increases the phosphorylation level of Janus kinase 2 (JAK2) and STAT3, enhancing the JAK2/STAT3 pathway, which attenuates H 2 O 2 -induced oxidative stress and suppresses apoptosis in glioma cells, and thus miR-33a overexpression inhibits apoptosis in glioma (Fig. 6A) (95). Wang et al (96) have demonstrated that miR-33a overexpression downregulates phosphodiesterase 8A (PDE8A) and UV radiation resistance associated (UVRAG), and upregulates their downstream proteins p-CREB and Notch intracellular domain, respectively, in glioma cells.…”

“…Studies have indicated that miR-33a acts as an oncogene in glioma. Chang et al ( 95 ) have revealed that miR-33a is upregulated in glioma cells. Consequently, the miR-33a target sirtuin 6 (SIRT6) is downregulated, reducing the levels of cleaved caspase 8 and BAX, and promoting Bcl-2 expression ( 95 ).…”