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

Abstract

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.

EXOSC8 promotes colorectal cancer tumorigenesis via regulating ribosome biogenesis-related processes

“…In contrast, EXOSC8 knockdown in p53 -/-CRC cells unchanged the binding of endogenous RPL5/11 to Mdm2, which is consistent with the previous report that p53 is necessary for the initial release of RPs from the nucleolus upon rRNA synthesis inhibition [18]. Intriguingly, other rRNA metabolism-related genes have also been reported to be involved in RPs-Mdm2-p53 ribosomal stress, including CNV gain-related overexpressed gene in tumors [29,33]. These results further highlight that the rRNA metabolism-related genes play important roles in ribosome biogenesis.…”

Downregulated RRS1 inhibits invasion and metastasis of BT549 through RPL11‑c‑Myc‑SNAIL axis

“…The dissociation of RPL11 from the ribosomal complex allows it to bind to c-Myc and inhibit its transactivation ( 41 ). There is also evidence that RRS1 knockout inhibits the nuclear export of RPL11 and increases its accumulation in the nucleus ( 30 ). Consistent with these previous observations, the present study found that RRS1 knockdown significantly enhanced the interaction between RPL11 and c-Myc ( Fig.…”

“…Increased ribosome biosynthesis is a prerequisite for sustaining the high proliferation rates of tumor cells ( 54 , 55 ). RRS1 is a regulator of ribosome biosynthesis and shows high expression levels in multiple tumors ( 14 , 24 - 28 , 30 ). Likewise, the present study also detected significantly higher levels of RRS1 in the breast cancer cell lines compared to normal breast epithelial cells.…”

“…Studies show that RRS1 also regulates chromosome rearrangement during mitosis ( 19 ) and telomere aggregation ( 20 ) and serves an important role in delayed cell aging ( 21 ) and in the development of Huntington's disease ( 22 ). In addition, RRS1 is abnormally expressed in various cancers ( 23 - 30 ). Through binding of RPL11, which inhibits the interaction between RPL11 and murine doubleminute 2 (MDM2), it promotes the proliferation of breast cancer cells and reduces p53 levels ( 26 ).…”

Pathogenesis of Choledochal Cyst: Insights from Genomics and Transcriptomics

“…Genes located in 3p23 and 8q13 were rearranged, indicating that the distal loss and/or gain of 8q may contribute to the pathogenesis of Caroli disease. Genomic gains of 8q can promote ribosome biogenesis activity, which promotes hepatocellular carcinoma development [ 41 , 42 ]. CC has a higher risk of malignancy transformation [ 43 , 44 , 45 ], although a link between chromosomal translocation t(3;8) leading to a gain of 8q13-qter and the risk of malignancy transformation in CC has yet to be established.…”