Genomic gain of RRS1 promotes hepatocellular carcinoma through reducing the RPL11-MDM2-p53 signaling

Hepatocellular carcinomas (HCCs) are characterized by frequent somatic genomic copy number alterations (CNAs), with most of them biologically unexplored. Here, we performed integrative analyses combining CNAs with the transcriptomic data to reveal the cis- and trans-effects of CNAs in HCC. We identified recurrent genomic gains of chromosome 8q, which exhibit strong trans-effects and are broadly associated with ribosome biogenesis activity. Furthermore, 8q gain–driven overexpression of ribosome biogenesis regulator (RRS1) promotes growth of HCC cells in vitro and in vivo. Mechanistically, RRS1 attenuates ribosomal stress through retaining RPL11 in the nucleolus, which, in turn, potentiates MDM2-mediated ubiquitination and degradation of p53. Clinically, higher RRS1 expression levels predict poor clinical outcomes for patients with HCC, especially in those with intact p53. Our findings established that the chromosome 8q oncogene RRS1 promotes HCC development through attenuating the RPL11-MDM2-p53 pathway and provided new potential targets for treatment of this malignancy.