Post-translational modifications (PTMs) can occur on specific amino acids localized within regulatory domains of target proteins, which control a protein’s stability. These regions, called degrons, are often controlled by PTMs, which act as signals to expedite protein degradation (PTM-activated degrons) or to forestall degradation and stabilize a protein (PTM-inactivated degrons). We summarize current knowledge of the regulation of protein stability by various PTMs. We aim to display the variety and breadth of known mechanisms of regulation as well as highlight common themes in PTM-regulated degrons to enhance potential for identifying novel drug targets where druggable targets are currently lacking.

Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8⁺ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8⁺ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8⁺ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.

Epigenetic regulation is important for establishing lineage-specific gene expression during early development. Although signaling pathways have been well-studied for regulation of trophectoderm reprogramming, epigenetic regulation of trophectodermal genes with histone modification dynamics have been poorly understood. Here, we identify that plant homeodomain finger protein 6 (PHF6) is a key epigenetic regulator for activation of trophectodermal genes using RNA-sequencing and ChIP assays. PHF6 acts as an E3 ubiquitin ligase for ubiquitination of H2BK120 (H2BK120ub) via its extended plant homeodomain 1 (PHD1), while the extended PHD2 of PHF6 recognizes acetylation of H2BK12 (H2BK12Ac). Intriguingly, the recognition of H2BK12Ac by PHF6 is important for exerting its E3 ubiquitin ligase activity for H2BK120ub. Together, our data provide evidence that PHF6 is crucial for epigenetic regulation of trophectodermal gene expression by linking H2BK12Ac to H2BK120ub modification.

Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.

Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from RORα-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in RORα-deficient embryonic fibroblasts, and reconstitution of RORα1 inhibited this activation by a NTD dependent manner. Downregulation of RORα1 and upregulation of Wnt/β-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated RORα1 signaling, suggesting advanced approaches for the development of therapeutic drugs.