May 7th

Recent Publications Harnessing the Power of Translatomics.

Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.

In this week’s Sunday papers, Kenski et al. aimed to investigate the failure of IDO1 inhibitors in clinical trials and the functional interactions between IDO1, epacadostat (an IDO1 inhibitor), tumor cells, and cytotoxic T cells. Zheng et al., used ribosome profiling and CRISPR/Cas9 knockout screening to identify cryptic lncRNA-encoded ORFs in breast cancer cells. Liu et al., investigated the developmental toxicity of BPC in zebrafish using a combination of techniques to determine the effects of BPC on zebrafish embryos and the underlying molecular mechanism. …

An adverse tumor-protective effect of IDO1 inhibition

Cell Reports Medicine, 2023
Kenski, J.C., Huang, X., Vredevoogd, D.W., de Bruijn, B., Traets, J.J., Ibáñez-Molero, S., Schieven, S.M., van Vliet, A., Krijgsman, O., Kuilman, T. and Pozniak, J.

Immune checkpoint blockade (ICB) has improved melanoma treatment, but therapy resistance limits its clinical benefits. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme, induced by interferon-gamma (IFNγ), that plays a role in acquired immune tolerance within the tumor microenvironment, leading to low tryptophan (TRP) levels and impairing cytotoxic T cell function. IDO1 inhibitors have been evaluated in clinical trials with anti-programmed cell death-1 antibodies, but the combination failed to improve progression-free survival. Therefore, the authors proposed further investigation to understand the failure of IDO1 inhibitors in clinical trials and the functional interactions between IDO1, epacadostat (an IDO1 inhibitor), tumor cells, and cytotoxic T cells.

RNA-seq was used to provide a global view of gene expression changes and pathway alterations in patient-derived melanoma cell lines with varying sensitivities to IFNγ. Following IFNγ treatment, the authors observed that genes involved in protein translation were downregulated in IFNγ-sensitive cell lines. Ribosome profiling confirmed an IFNγ induced decrease in protein translation in D10, an IFNγ-responsive human melanoma cell line. Ribosome profiling also identified that IFNγ treatment caused ribosome stalling at the TRP codon, confirming that this general inhibition of translation is driven by TRP depletion. Notably, these effects were completely reversed by co-treatment with epacadostat.

The resulting stress response to IFNγ induced tryptophan deprivation selectively increases activating transcription factor-4 (ATF-4) translation which in turn is associated with reduced expression of microphtalmia-associated transcription factor (MITF), a known survival factor for melanoma cells. The sensitivity of the tumor cells to T cell attack was strongly associated with their ability to downregulate MITF. Notably, epacadostat resulted in the upregulation of MITF.

The findings from this study not only reveals a potential negative impact of inhibiting IDO1, but also suggests that therapeutic intervention targeting MITF may be a viable strategy to enhance the effectiveness of immunotherapy in melanoma patients.

CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer

Journal of Clinical Investigation, 2023
Zheng, C., Wei, Y., Zhang, P., Xu, L., Zhang, Z., Lin, K., Hou, J., Lv, X., Ding, Y., Chiu, Y. and Jain, A.

The ENCODE/GENCODE project has discovered that over 70% of the human genome is transcribed, resulting in a complex repertoire of transcripts that include long non-coding RNAs (lncRNAs). Although lncRNAs were previously thought to not code for proteins, recent evidence suggests that a fraction of them can encode cryptic proteins. This study uses ribosome profiling and CRISPR/Cas9 knockout screening to identify cryptic lncRNA-encoded ORFs in breast cancer cells. The researchers identify a cryptic protein, called GT3-INCP, encoded by the LINC00992 lncRNA that interacts with GATA3 and could play a role in breast cancer development.

In this study, ribosome profiling was used to identify cryptic ORFs within long non-coding RNAs that are actively translated in estrogen receptor α-positive (ER+) breast cancer (BC) cells. The researchers were able to identify 28 functional cryptic ORFs encoded by lncRNAs that are upregulated in luminal BC compared to normal breast tissue. They further validated the tumor-promoting functions of two of these cryptic ORFs, which are encoded by LINC00992 and GATA3-AS1. These findings suggest that some of the identified functional cryptic ORFs might play an important role in therapeutic resistance of ER+ BC. Additionally, the study reveals that lncRNA-encoded proteins can play an important role in transcriptional regulation, as shown by the interaction of GT3-INCP with GATA3 to coregulate the expression of BC susceptibility genes and/or genes key to the growth/proliferation of ER+ BC cells.

The study demonstrates the essential role of lncRNA-encoded proteins in transcriptional regulation and highlights the potential of the cryptic proteome encoded by lncRNAs as an untapped space for therapeutic target discovery.

Bisphenol C induces developmental defects in liver and intestine through mTOR signaling in zebrafish (Danio rerio)

Chemosphere, 2023
Liu, J., Lin, J., Chen, J., Maimaitiyiming, Y., Su, K., Sun, S., Zhan, G. and Hsu, C.H

Bisphenol A (BPA) is a raw material used in the production of various daily necessities and can leach from food and beverage containers, posing a risk to human health and the environment. BPA substitutes have emerged, but their potential developmental toxicity is unclear. Bisphenol C (BPC) is a common substitute for BPA and is found in human samples and the environment. Studies have shown that BPC induces oxidative damage, apoptosis, spinal malformation, and genital abnormalities. This study investigated the developmental toxicity of BPC in zebrafish using a combination of techniques to determine the effects of BPC on zebrafish embryos and the underlying molecular mechanism.

The researchers exposed zebrafish embryos to different concentrations of BPC and assessed the effects on liver and intestinal development using histological and immunofluorescence techniques. They found that BPC induced developmental defects in the liver and intestine, including abnormal growth, structure, and function. Further, RNA sequencing was used to analyze the global gene expression changes induced by BPC exposure. They found that BPC exposure led to changes in the expression of genes involved in cell proliferation, differentiation, and metabolism, which could contribute to the observed developmental defects. Moreover, polysome profiling analyses were carried out to verify whether BPC exposure affects translation efficiency, and the results showed that BPC exposure resulted in a translational defect. The translation of essential genes for cell proliferation in the liver and intestine was also detected, and the polysome profiling assay showed that BPC exposure promoted the transfer of yap1 and tcf4 mRNA from heavier to lighter polysomal fractions, confirming the translation defect of these two liver and intestinal essential genes.

Finally, the researchers investigated the underlying molecular mechanism of BPC-induced developmental defects. They focused on the mechanistic target of rapamycin (mTOR) signaling pathway, which regulates cell proliferation and differentiation. They found that BPC exposure led to downregulation of mTOR signaling and decreased phosphorylation of its downstream molecule ribosomal protein S6 (RPS6), which reduced translation of cell proliferation-related genes and contributed to liver and intestinal developmental defects.

Overall, this study provides insights into the potential adverse effects of BPC and suggests a therapeutic strategy for dealing with them.

Oscar Ting

Oscar Ting

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