TY - JOUR
T1 - Dissecting the effects of METTL3 on alternative splicing in prostate cancer
AU - Wang, Lin
AU - Shi, Ling
AU - Liang, Yonghao
AU - Ng, Judy Kin Wing
AU - Yin, Chan Hoi
AU - Wang, Lingyi
AU - Hou, Jinpao
AU - Wang, Yiwei
AU - Fung, Cathy Sin Hang
AU - Chiu, Peter Ka Fung
AU - Ng, Chi Fai
AU - Tsui, Stephen Kwok Wing
N1 - Publisher Copyright:
Copyright © 2023 Wang, Shi, Liang, Ng, Yin, Wang, Hou, Wang, Fung, Chiu, Ng and Tsui.
PY - 2023
Y1 - 2023
N2 - Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker.
AB - Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker.
KW - METTL3
KW - MKNK2
KW - N 6 -methyladenosine
KW - RNA splicing
KW - nanopore direct RNA sequencing
KW - prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85169663828&partnerID=8YFLogxK
U2 - 10.3389/fonc.2023.1227016
DO - 10.3389/fonc.2023.1227016
M3 - Article
AN - SCOPUS:85169663828
VL - 13
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1227016
ER -