The Interplay Between the MYC Oncogene and Ribosomal Proteins in Osteosarcoma Onset and Progression: Potential Mechanisms and Indication of Candidate Therapeutic Targets

Abstract

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65-70%, dropping down to 20% when metastases are present at diagnosis. Therefore, curing OS is a clinical challenge, particularly for patients that do not respond to standard treatments. MYC has frequently been reported to be involved in the pathogenesis of OS and its high expression may be associated with drug resistance and patients' worse prognosis. Moreover, MYC is a master regulator of ribosomal proteins (RPs) synthesis and ribosome biogenesis (RiBi), which is often up-regulated in human tumors. In recent years, RPs have been recognized not only for their traditional role in ribosome assembly but also for their extra-ribosomal functions, many of which are linked to the onset and progression of cancer. In this review we focus on the role and possible interplay of MYC and RPs expression in association with drug resistance and worse prognosis in OS and discuss therapeutic options that target de-regulated MYC, RiBi, or RPs, which are already clinically available or under evaluation in clinical trials.

Keywords: MYC; osteosarcoma; ribosomal proteins.

Figure 1

MYC and RiBi. MYC acts at different levels of RiBi by regulating RNA Pol I, II, and III. (1) Heterodimer of MYC-MAX promotes rDNA transcription by interacting with TBP and TAFs to recruit Pol I. Moreover, MYC interacts with cofactors like TRRAP and promotes histone acetylation to activate rDNA transcription. (2) MYC activates 5S rRNA and tRNA transcription via Pol III by directly engaging TFIIIB. (3) MYC also stimulates the transcription of genes involved in ribosomal biogenesis and translation through Pol II by interacting with chromatin remodelers.

Figure 2

Highlights of the most important implications and consequences of MYC alterations in OS.