ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression

by Selleckchem | Sep 25 2023

Aberrant N6-methyladenosine (m6A) modification of mRNAs contributes significantly to the epigenetic tumorigenesis, however, its precise role and the key targets in osteosarcoma (OS) are not defined. Here we reported that selective METTL3 (methyltransferase like 3) elevation and the consequential increase of m6A modification causally affect OS progression. The fast-growing OS cells displayed preferential upregulation of METTL3 and increased m6A modification. Conversely, m6A inhibition by 3-deazaadenosine, siRNA-mediated METTL3 knockdown or a METTL3-selective inhibitor by STM2457 effectively inhibits OS cell growth and induced OS cell apoptosis. Further investigation revealed that an oncogenic protein ZBTB7C was likely a critical m6A target that mediated the oncogenic effects. ZBTB7C mRNA contains a typical m6A motif of high confidence and its mRNA and protein were enriched with increased m6A modification in OS samples/cells. In an OS xenograft model, STM2457 or siRNA-mediated METTL3 knockdown effectively lowed ZBTB7C abundance. More importantly, the anti-OS effects of STM2457 were significantly reduced when ZBTB7C was overexpressed by lentivirus. Together, our results demonstrate that the METTL3 aberration and the resultant ZBTB7C m6A modification form an important epigenetic regulatory loop that promotes OS progression, and targeting the METTL3/ZBTB7C axis may provide novel insights into the potential strategies for OS therapy.

Comments:

The passage you provided describes a study that investigated the role of aberrant N6-methyladenosine (m6A) modification in the development and progression of osteosarcoma (OS), a type of bone cancer. The study focused on the enzyme METTL3 (methyltransferase like 3) responsible for m6A modification and its potential impact on OS.

The researchers found that OS cells with a fast growth rate exhibited increased levels of METTL3 and enhanced m6A modification. To understand the significance of this, they conducted experiments inhibiting m6A modification using 3-deazaadenosine, siRNA-mediated METTL3 knockdown, or a METTL3-selective inhibitor called STM2457. Inhibition of m6A modification resulted in the inhibition of OS cell growth and induced apoptosis (cell death).

Further investigation revealed a potential target of m6A modification in OS, an oncogenic protein called ZBTB7C. The mRNA of ZBTB7C contained a characteristic m6A motif, and both its mRNA and protein levels were enriched with increased m6A modification in OS samples and cells.

To validate the significance of ZBTB7C in OS progression, the researchers used an OS xenograft model and demonstrated that STM2457 or siRNA-mediated METTL3 knockdown effectively reduced the abundance of ZBTB7C. Importantly, when ZBTB7C was overexpressed using lentivirus, the anti-OS effects of STM2457 were significantly reduced.

Overall, the study suggests that aberrant METTL3 elevation and subsequent m6A modification, particularly on the ZBTB7C mRNA, contribute to the progression of OS. The findings highlight the METTL3/ZBTB7C axis as an important epigenetic regulatory loop involved in OS and propose targeting this axis as a potential strategy for OS therapy.