LINC-PINT suppresses cisplatin resistance in gastric cancer by inhibiting autophagy activation via epigenetic silencing of ATG5 by EZH2

Abstract

Resistance to cisplatin (DDP) is a major obstacle in the clinical treatment of advanced gastric cancer (GC). Long noncoding RNA (lncRNA) play a significant regulatory role in the development and drug resistance of GC. In this study, we reported that the lncRNA LINC-PINT was downregulated in DDP-resistant GC cells. Functional studies showed that LINC-PINT inhibited proliferation and migration of DDP-resistant GC cells in vitro, and overexpression of LINC-PINT could enhance the sensitivity of DDP-resistant GC cells to DDP. Further investigation revealed that LINC-PINT recruited enhancer of zeste homolog 2 (EZH2) to the promotor of ATG5 to inhibit its transcription, leading to the suppression of autophagy and DDP resensitization. Collectively, our results revealed how the LINC-PINT/EZH2/ATG5 axis regulates autophagy and DDP resistance in GC. These data suggest that LINC-PINT may be a potential therapeutic target in GC.

YTHDF2 exerts tumor-suppressor roles in gastric cancer via up-regulating PPP2CA independently of m6A modification

“…Drug tolerance remains a barrier to eligibility for cancer chemotherapy, and resistance to cisplatin is a major handicap to the clinical treatment of late-stage gastric cancer [ 17 ]. To test whether YTHDF2 overexpression influenced cisplatin resistance, HGC27 and MGC803 cells with YTHDF2 stable overexpression (LV-YTHDF2) were cultured with cisplatin followed by colony formation assays and we found that YTHDF2 overexpression increased the cisplatin sensitivity of GC cells (Fig.…”

Lnc-PTCHD4-AS inhibits gastric cancer through MSH2-MSH6 dimerization and ATM-p53-p21 activation

“…Furthermore, the expression of PINT was found to be reduced in cases of colorectal cancer, whereas increased expression of PINT was observed to hinder the proliferation of tumor cells [ 47 ]. Subsequent investigations have provided additional evidence indicating that long non-coding RNA PINT has a regulatory influence on the proliferation of tumor cells and their sensitivity to radiochemotherapy across a range of malignancies [ 48 ], including gastric cancers [ 49 ], nasopharyngeal cancers [ 50 ], and skin cancers [ 51 ], and serves as a diagnostic/prognostic marker of cancer [ 52 , 53 ].…”

“…CDDP is a first-line chemotherapeutic regimen that induces DNA damage and activates cell cycle checkpoints primarily through forming platinum-DNA polymers, leading to apoptosis of cancer cells [ 49 , 61 , 62 ]. It has been known that the MSH2- MSH6 dimer recognizes cisplatin, and its functional defects can enhance resistance to cisplatin [ 63 ].…”

Long Non-Coding RNAs in Drug Resistance of Gastric Cancer: Complex Mechanisms and Potential Clinical Applications

“…In DDP-resistant GC cell lines, 12 lncRNAs were found to be involved in the regulation and promotion of invasion and metastasis. They are HOTAIR [ 60 , 61 , 62 ], HOTTIP [ 65 ], FAM84B-AS [ 48 ], KLF3-AS1 [ 69 ], SNHG6 [ 93 ], ST7-AS1 [ 106 ], LINC-PINT [ 72 ], and LINC00922 [ 73 ]. Six lncRNAs are implicated in the multidrug resistance of gastric cancer cells and facilitate the invasion and metastasis of these drug-resistant cells.…”