Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer


Worldwide, bladder cancer is the 11th most common malignancy, with more than 570,000 new cases and 210,000 deaths annually, and the incidence is increasing. Urothelial cell bladder cancer accounts for 90% of bladder cancer cases worldwide and is especially common in developed nations. This subtype is highly associated with chemical exposure, such as occupational exposure or tobacco smoke, due to urothelial direct exposure. Histologically, bladder cancer comprises 75% pure urothelial carcinoma and 25% “variant” histology, complicating this illness’s therapy.

M6A RNA alteration describes adenosine methylation at the N6 position and is the most common internal alteration in eukaryotic mRNA. Two essential catalytic proteins, demethylases (writers) and methyltransferases, control the m6A modification of RNA dynamically and reversibly (erasers). M6A alterations have an impact on RNA maturation, transcription, localization, translation, and metabolism. The most common mRNA alteration is N6-methyladenosine (m6A), which is done by the methyltransferase complex, methyltransferase-like 3 (METTL3) the single catalytic component. Recent data suggest that METTL3 plays an important role in many cancer types, either reliant or independent of its m6A RNA methyltransferase activity. While the roles of m6A alterations in cancer have been explored elsewhere, the crucial functions of METTL3 in many forms of cancer and the potential targeting of METTL3 as cancer therapy have yet to be addressed.

The epigenetic mechanisms by which melittin affects RNA methylation and its influence on cancer growth remains unknown. In a new study published in the journal Cancer Letters, Shanghai Medical College researchers: Rucheng Yan, Weiwei Dai, Ruixin Wu, Houbao Huang, and led by Professor Minfeng Shu found that melittin preferentially triggered apoptosis of bladder cancer cells in a METTL3-dependent pathway. Investigators discovered that METTL3 ectopic expression greatly inhibited melittin-induced apoptosis in vitro and in vivo.

The research team showed that disruption of the METTL3/miR-146a-5p pathway leads to the development of bladder cancer. Furthermore, melittin-induced selective METTL3 suppression reduces miR-146a-5p in an m6A-dependent manner, activating the NOTCH2 pathway and inducing bladder cancer cell death. This is the first reported evidence that the m6A-modified NOTCH pathway promotes bladder cancer growth and facilitates melittin-induced tumour suppression. Surprisingly, the relapse bladder cancer tissues had decreased NUMB expression, indicating that NUMB depletion may be implicated in bladder cancer recurrence.

Moreover, when the authors looked at 41 bladder cancer tissues, NUMB expression was inversely linked with METTL3 protein level. They also showed that NOTCH2 was overexpressed in bladder cancer tumour tissues relative to normal tissues, and NUMB was a direct downstream target of miR-146a-5p that inhibited the development of bladder cancer by suppressing NOTCH2 in bladder cancer cells. Although the current study did not find an effect of miR-146a-5p on NOTCH1 expression, it is reasonable to believe that miR-146a-5p may also target NOTCH1, which works as a tumour suppressor in bladder cancer cells. Based on the specific NOTCH2 suppression mechanism, the authors hypothesized that miR-146a-5p inhibitors and melittin might be attractive bladder cancer therapeutic choices.

Furthermore, the authors conducted an experiment where they incubated melittin (4 g/ml) in various cell types, for example, it resulted in significant apoptosis in T24 and EJ cells  but had no effect on BIU87 and SV-HUC-1 cells, indicating that there may be a separate mechanism that causes the selective tumour suppression. Melittin significantly reduced m6A levels by selectively suppressing METTL3 expression, and bladder cancer cells (T24 and EJ) with high endogenous METTL3 expression were more responsive to melittin treatment. Furthermore, METTL3 overexpression significantly increased apoptosis in melittin-resistant BIU87 cells exposed to melittin.

In conclusion, the study by Professor Minfeng Shu and colleagues revealed a unique m6A-mediated epigenetic pathway for melittin-induced selective bladdercancer suppression in vitro and in vivo. Furthermore, the study demonstrsated the importance of the METTL3/miR-146a- 5p/NUMB/NOTCH2 axis in bladder cancer progression and possibly a good therapeutic target for recurrent bladder cancer therapy.

Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer - Medicine Innovates

About the author

Minfeng Shu, M.D & Ph.D.
Department of Pharmacology
Key Laboratory of Medical Molecular Virology, Ministry of Education (MOE) & National Health Commission (NHC)
School of Basic Medical Sciences
Shanghai Medical College
Fudan University
131 Dong’an Road, Shanghai, 200032, PR China

Dr. Shu received his M.D. degree (Clinical Medicine) from Wannan Medical College in 2006, and a Ph.D. degree (Pharmacology) from Sun Yat-sen University in 2011. From 2011 to 2017, he was a postdoctoral scholar (Virology and Oncology) at The University of Chicago. He joined the faculty at Fudan University in 2017.

Dr. Shu ‘s research interests focused on the epigenetic regulation of tumor microenvironment and gene therapy, particularly on regulation of RNA modification and metabolism and on the use of the herpes simplex virus to remodel tumor-immune microenvironment.


Yan R, Dai W, Wu R, Huang H, Shu M. Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer. Cancer letters. 2022 May 28;534:215615.

Go To Cancer letters.