Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9

Abstract

In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3β/β-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3β, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3β protein. Increased GSK3β expression stimulated the β-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3β/β-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

“…In previous studies, miRNAs have been widely reported to be regulated by various transcription factors. 39 , 40 , 41 , 42 Sp1 belongs to a famous Sp transcription family, which also includes Sp2 , Sp3 , and Sp4 , and it has been importantly proven to modulate essential biological processes such as cell growth, 43 differentiation, 44 and apoptosis and carcinogenesis. 45 For many cancer patients, elevated Sp1 expression is considered as an adverse prognostic factor.…”

Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma

“…Non-muscle myosin heavy chain IIA (MYH9) is involved in many biological processes, including cell migration, adhesion, division, polarity, and morphogenesis. 3 MYH9 is dysregulated and serves as an oncogene in many cancers; [4][5][6][7][8][9][10] however, its expression is positively associated with a good prognosis in patients with head and neck squamous cell carcinomas. 11 Moreover, researchers have reported that MYH9 promotes cell invasion and metastasis in gastric cancer, 12,13 facilitates cell growth and metastasis in colorectal cancer and pancreatic cancer, 14,15 and induces drug resistance in neuroblastoma.…”

SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma

“…In prior study, we have shown that SPEN induces mir-465-3p expression, However, the mechanism by which SPEN regulates miR-4652-3p expression has not been elucidated. It is well known that transcript factor-mediated miRNA transcription expression has been widely documented in tumors 11 , 20 , 25 . In this study, we first predicted the possible transcription factors binding to the miR-4652-3p promoter.…”

“…MicroRNAs (miRNAs) area class of small (17–23 nucleotides) noncoding RNAs that silence mRNA molecules through a degradation or translational inhibition process. They participate in various biological processes, including tumorigenesis and metastasis 11 – 13 . Multiple miRNAs have been found to play key roles in regulating the expression of various critical genes during the development of human tumors 4 , 14 , 15 .…”