Regulation of Nucleolar Activity by MYC

Abstract

The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity is elevated due to their high demand for protein synthesis. The transcription factor and universal oncogene MYC promotes nucleolar activity by enhancing the transcription of ribosomal DNA (rDNA) and ribosomal proteins. This review summarizes the importance of nucleolar activity in mammalian cells, MYC’s role in nucleolar regulation in cancer, and discusses how a better understanding (and the potential inhibition) of aberrant nucleolar activity in cancer cells could lead to novel therapeutics.

ZNF692 organizes a hub for ribosome maturation enhancing translation in rapidly proliferating cells

“…MYC has been causally related to tumor initiation and maintenance in part due to its potent capacity to boost ribosome biogenesis 26 . MYC upregulates genes involved in all of the steps of ribosome biogenesis from rDNA transcription to rRNA maturation and genes encoding ribosomal proteins 9, 59 . This connection between ribosome biogenesis and tumorigenesis is also apparent in genetic disorders with predisposition to tumor development.…”

“…Dysregulation of ribosome biogenesis is reflected by alterations in nucleolar morphology 2,3 and can lead to a variety of human diseases including Alzheimer's, Parkinson's, Huntington's diseases, Diamond Blackfan Anemia, and Treachers-Collins Syndrome [1][2][3][4][5][6][7][8] . Increased nucleolar size and activity are associated with augmented ribosome production in cancer cells 9 . Indeed, having more and larger nucleoli is the most distinguishable morphological alteration of a cancer cell and is frequently used by pathologists to grade solid tumors 10,11 .…”

“…Numerous studies have shown that the transcription factor MYC promotes ribosome biogenesis 26,27 by driving rDNA transcription, regulating the transcription of structural and regulatory components of the ribosome, and amplifying RNAPol III-mediated 5S rRNA production 9,[28][29][30] . Moreover, MYC-induced transformation was found to be dependent on increased ribosome biogenesis and protein synthesis 27 .…”

Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs

“…FBL-overexpressing cells acquired anchorage-independent proliferation and even resistance to doxorubicin in one cell line [ 137 ]. FBL was observed to be regulated by p53, which suppresses its nucleolar function through direct binding to elements on intron 1 of the FBL gene, and Myc [ 137 , 138 ]. The downregulation of p53 or a significant loss of function—especially as a characteristic of the mutant phenotype—appeared to prevent this regulation, causing FBL overexpression and modulating FBL activity at known methylation sites, which correlated with increased tumorigenesis and colony-forming capabilities in breast cancer tumors via increased FBL and IGF1R-embedded IRES, a noncanonical initiator of protein translation whose expression is necessary for FBL-induced proliferation [ 133 , 137 ].…”

OST-01, a natural product from Baccharis coridifolia, targets c-Myc-dependent ribogenesis in acute myeloid leukemia

“…S2A-D). Given that c-Myc regulates nucleolar assembly and aberrant expression of c-Myc promotes cancer cell growth through increase of ribosomal biogenesis [7][8][9], we hypothesized that OST-01-disrupted c-Myc regulated nucleolar structure and ribosome biogenesis is one of its antileukemic MOAs. A twenty-four-hour exposure to OST-01 resulted in a significantly decreased levels of c-Myc and other nucleolar proteins i.e., NPM1, nucleostemin and nucleolin, (Fig.…”