hMTR4 promotes p53 protein degradation and tumor growth by accelerating rRNA processing and regulating the RPL5-MDM2 axis

hMTR4 is an RNA helicase and an essential co-factor for the nuclear RNA exosome. Its role in the p53 pathway and cell cycle control remains unknown. Here, gain- and loss-of-function analyses in cell models showed that hMTR4 could not affect p53 mRNA levels, but decreased the levels of p53 protein and its downstream target genes by promoting p53 ubiquitination and degradation, thus accelerating cell cycle progression. These effects of hMTR4 were abrogated by nutlin-3A, an inhibitor of E3 Ligase MDM2. Mechanistically, hMTR4 promoted rRNA processing in an RNA helicase-dependent manner, thus increased the amount of mature rRNA to bind ribosomal protein L5 (RPL5), resulted in sequestration of RPL5 in the nucleolus and reduced binding of RPL5 to MDM2 in the nucleoplasm, consequently promoted MDM2-mediated degradation of p53 protein. Silencing RPL5 blocked the effect of hMTR4 knockdown in upregulating p53, while hMTR4 overexpression abrogated the role of RPL5 in stimulating p53 activity. Interestingly, hMTR4 reduced the mRNA levels of p53-target genes via repressing p53 activity rather than promoting their RNA degradation. These findings disclose a novel hMTR4-rRNA-RPL5-MDM2-p53 axis and highlight hMTR4 and rRNA processing as important regulators of the p53 pathway. Further investigations on clinical samples showed that hMTR4 and RPL5 were frequently upregulated in different malignancies, including hepatocellular carcinoma (HCC), and they exhibited a positive correlation. High hMTR4 level was correlated with high recurrence of HCC, among patients with high RPL5 levels and wildtype p53 in tumors. Studies using mouse xenograft models revealed that silencing Skiv2l2 (the homologue of human hMTR4) in mouse hepatoma cells inhibited xenograft development, and tumor growth was suppressed by intratumoral injection of Antisense Oligonucleotides (ASO) targeting Skiv2l2. These data suggest the significance of hMTR4 overexpression in promoting tumor growth and its potential as a therapeutic target.