N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway

Abstract

Background Pancreatic cancer (PC) is highly malignant. Chemotherapy is the main treatment strategy, especially for patients with advanced PC. However, chemoresistance has always been a frequently encountered bottleneck. Hence, there is an urgent need to enhance the sensitivity of PC to gemcitabine (GEM). Results We demonstrated that SH3BP5-AS1 was significantly upregulated in GEM-resistant PC and predicted a poorer prognosis. SH3BP5-AS1 stability was regulated by ALKBH5/IGF2BP1-mediated m6A modification. Loss of SH3BP5-AS1 reduced PC cell migration and invasion and enhanced the sensitivity of PC to GEM, as confirmed by gain- and loss-of-function assays in vitro and in vivo. Bioinformatics analysis revealed that SH3BP5-AS1 acted as a ceRNA against miR-139-5p and directly targeted CTBP1, affecting the biological behavior of PC cells. The mechanistic studies revealed that the upregulation of SH3BP5-AS1 increased CTBP1 expression by directly activating the Wnt signaling pathway, promoting GEM resistance. Conclusions This study revealed that SH3BP5-AS1 activated Wnt signaling pathway by sponging miR-139-5p, upregulating CTBP1 expression, and contributing to the sensitivity of PC cells to GEM. SH3BP5-AS1 might be a potential target for PC therapy.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A‐dependent DAPK3 degradation

“… 42 Dysregulation of m6A also contributes to the development of gemcitabine resistance. 43 Moreover, the effect of DAPK3 on chemotherapy resistance has been well established in previous studies, which induces the loss of cell‐to‐cell adhesion, thereby conferring more sensitivity to chemotherapy. 26 , 27 Consistent with this evidence, we observed that YTHDF2 mediated resistance to gemcitabine in GBC cells through DAPK3.…”

“…In ovarian cancer, Nicotinamide N‐methyltransferase (NNMT) mRNA is demethylated and upregulated by Fat mass and obesity‐associated protein (FTO), thereby increasing sensitivity to platinum 42 . Dysregulation of m6A also contributes to the development of gemcitabine resistance 43 . Moreover, the effect of DAPK3 on chemotherapy resistance has been well established in previous studies, which induces the loss of cell‐to‐cell adhesion, thereby conferring more sensitivity to chemotherapy 26,27 .…”

New insights into the interaction between m6A modification and lncRNA in cancer drug resistance

“…Similarly, Lin illustrated that lncRNA SH3BP5‐AS1 was significantly upregulated in gemcitabine‐resistant pancreatic cancer cells and this upregulation was found to be associated with a poor prognosis for PC patients. Mechanistically, the stability of SH3BP5‐AS1 was negatively regulated by ALKBH5/IGF2BP1‐mediated m6A modification 131 . Furthermore, increased m6A‐modified lncRNA DBH‐AS1 suppressed GEM resistance in pancreatic cancer.…”

“…Mechanistically, the stability of SH3BP5‐AS1 was negatively regulated by ALKBH5/IGF2BP1‐mediated m6A modification. 131 Furthermore, increased m6A‐modified lncRNA DBH‐AS1 suppressed GEM resistance in pancreatic cancer. DBH‐AS1 increased sensitivity of PC cells to GEM by sponging miR‐3163 and upregulating USP44 in PC cells.…”

New understandings of the genetic regulatory relationship between non-coding RNAs and m6A modification

“…A handful of lncRNAs have been discovered to modulate m 6 A writers as well. The lncRNA UCA1, for example, accelerates the course of acute myeloid leukemia by connecting to METTL14 to elevate m6A quantities and augment CXCR4 and CYP1B1 expression ( Li et al, 2022a ). Nevertheless, the modulation of m 6 A erasers associated with lncRNAs has only occasionally been documented, which could offer fresh perspectives on the course of future research and open up opportunities for the treatment of cancer.…”