Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Alternative polyadenylation (APA) regulates gene expression and 3' untranslated region (3'UTR) length.
• APA reprogramming is prevalent in kidney renal clear cell carcinoma (KIRC), but its functional role is unclear.
• Chromatin modifiers are increasingly implicated in cancer development.

Purpose of the Study:

• To investigate the role of APA reprogramming in KIRC pathogenesis.
• To identify key genes and regulatory pathways involved in APA-driven KIRC.
• To explore therapeutic strategies targeting the identified APA regulatory axis.

Main Methods:

• Analysis of APA patterns in KIRC patient samples.
• Identification of genes with APA reprogramming using bioinformatics.
• Experimental validation of MORC2 and NUDT21 functions in KIRC cell lines and animal models.
• Development and testing of an antisense oligonucleotide (ASO) therapy.

Main Results:

• MORC2 exhibits oncogenic potential in KIRC, with its 3'UTR shortening stabilizing MORC2 mRNA.
• MORC2 downregulates tumor suppressor DAPK1 via DNA methylation, recruiting DNMT3A.
• Loss of APA regulator NUDT21, due to DNMT3B-mediated methylation, causes MORC2 3'UTR shortening.
• NUDT21 functions as a tumor suppressor by downregulating MORC2.
• An ASO targeting NUDT21 demonstrated in vitro and in vivo antitumor activity.

Conclusions:

• Uncovered a novel DNMT3B/NUDT21/APA/MORC2/DAPK1 regulatory axis in KIRC.
• Demonstrated the functional significance of APA reprogramming and its interplay with DNA methylation in KIRC.
• Validated NUDT21 as a tumor suppressor and proposed ASO-mediated NUDT21 restoration as a potential KIRC therapy.