Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis

Abstract

Background Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. Methods The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. Results AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. Conclusions In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance.

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

“…USP3 is also recruited by a novel lncRNA, AC092894 .1, to promote AR (androgen receptor) deubiquitination and, subsequently, chemosensitivity to oxaliplatin[ 87 ].…”

A novel lncRNA LOC101928222 promotes colorectal cancer angiogenesis by stabilizing HMGCS2 mRNA and increasing cholesterol synthesis

“…Subsequently, the cells were fixed with 4% PFA paraformaldehyde, washed and added with prehybridization solution at 65 °C for 1 h. Then the hybridization solution containing the probe was added and reacted in the dark at 65 °C in a hybridizer for 48 h. The cells were washed with 4× and 2× SSC, and then subjected to DAPI staining. The slices were observed by fluorescence microscopy after sealed [ 23 , 24 ]. RNA FISH probes were designed and synthesized by Ribobio (Guangzhou, China).…”

“…Protein bands were visualized using an ECL substrate and a fully automated chemiluminescence imaging analysis system. GAPDH was used as the internal reference [ 24 ].…”

Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases

“…USP3 can also impact CRC sensitivity to oxaliplatin by mediating the USP3/AR/RASGRP3 axis. USP3 promotes transcription of RASGRP3 by deubiquitinating and stabilizing the transcription factor AR, and up-regulation of RASGRP3 increases CRC sensitivity to oxaliplatin [ 69 ]. However, research of Alkhizzi et al reveals that both linear and circular isoforms of USP3 are upregulated in CRC.…”