lnc122 RNA prevents liver tumorigenesis in MYC-driven liver cancer.

BACKGROUND & AIMS: Extensive research has shown that the microRNA-122 (miR-122) plays an important role in liver homeostasis, and its dysregulation has been implicated in various liver pathologies such as liver cancer and non-alcoholic fatty liver disease. The primary transcript for miR-122, long non-coding RNA 122 (lnc122) has traditionally only been considered an intermediate product for mature miR-122.

METHODS

We used CRISPRi to inhibit lnc122 RNA expression in hepatoma cells and mouse livers with and without expression of mature miR-122 RNA to determine if a lnc122 RNA has a separate function. These models were used in combination of RNA-seq, Gene Set Enrichment Analysis, RNA pulldown-mass spectrometry, and a CRSIRPi/CRISPRa mediated liver tumor model to establish the specific role of lnc122 in hepatic homeostasis.

RESULTS

We demonstrate that lnc122 RNA has a distinct tumor suppressive role that is separate from the antiproliferative function of miR-122. Specifically, lnc122 RNA promotes MYC protein degradation by stabilizing the MYC-UBR5 E3 ubiquitin ligase protein complex. Unlike other E3 ubiquitin ligases for MYC, UBR5 is co-amplified with MYC in >40% of human cancers because of their close location on the human genome and lnc122 is indispensable for efficient MYC degradation by UBR5. Paired patient liver and tumor samples showed decreased concentrations of lnc122 RNA in tumors. Furthermore, reducing the lnc122 RNA transcripts in mouse liver exacerbated MYC-driven liver tumorigenesis. Although lnc122 expression is restricted to the liver, exogenous expression of lnc122 in non-hepatic transformed cells also destabilized MYC protein.

CONCLUSIONS

Our findings indicate that lnc122 RNA has a synergistic role with miR-122 in the surveillance and prevention of liver tumorigenesis and may represent a new target for treating MYC-driven human cancers.

IMPACT AND IMPLICATIONS: The study demonstrates that lnc122 RNA not only is a precursor for miR-122, but also functions in forming a ubiquitination complex via UBR5, and responsible for limiting the half-life of MYC protein. Loss of lnc122 RNA expression promotes liver cancer perhaps categorizing it as tumor suppressor gene. Further studies to develop agents to enhance the activity of this complex may offer a new therapeutic approach to treat hepatocellular carcinoma.