Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiological and pathological roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro-oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Additionally, NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways.
Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3′ untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3′ UTR of NR4A2 that was responsible for miR-34–mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer-related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2.
BackgroundThe target of rapamycin complex 1 (TORC1) is an evolutionarily conserved signal transduction pathway activated by environmental nutrients that regulates gene transcription to control cell growth and proliferation. How TORC1 modulates chromatin structure to control gene expression, however, is largely unknown. Because TORC1 is a major transducer of environmental information, defining this process has critical implications for both understanding environmental effects on epigenetic processes and the role of aberrant TORC1 signaling in many diseases, including cancer, diabetes, and cardiovascular disease.ResultsTo elucidate the role of TORC1 signaling in chromatin regulation, we screened a budding yeast histone H3 and H4 mutant library using the selective TORC1 inhibitor rapamycin to identify histone residues functionally connected to TORC1. Intriguingly, we identified histone H3 lysine 37 (H3K37) as a residue that is essential during periods of limited TORC1 activity. An H3K37A mutation resulted in cell death by necrosis when TORC1 signaling was simultaneously impaired. The induction of necrosis was linked to alterations in high mobility group (HMG) protein binding to chromatin. Furthermore, the necrotic phenotype could be recapitulated in wild-type cells by deregulating the model HMG proteins, Hmo1 or Ixr1, thus implicating a direct role for HMG protein deregulation as a stimulus for inducing necrosis.ConclusionsThis study identifies histone H3 and H4 residues functionally required for TORC1-dependent cell growth and proliferation that are also candidate epigenetic pathways regulated by TORC1 signaling. It also demonstrates a novel role for H3K37 and TORC1 in regulating the binding of select HMG proteins to chromatin and that HMG protein deregulation can initiate a necrotic cell death response. Overall, the results from this study suggest a possible model by which chromatin anchors HMG proteins during periods of limited TORC1 signaling, such as that which occurs during conditions of nutrient stress, to suppress necrotic cell death.
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