Enhanced nuclear translation is associated with proliferation and progression across multiple cancers

Abstract

Recent technological advances have re‐invigorated the interest in nuclear translation (NT), but the underlying mechanisms and functional implications of NT remain unknown. Here we show that NT is enhanced in malignant cancer cells and is associated with rapid cell growth. Nuclear ribopuromycylation analyses in a panel of diverse cell lines revealed that NT is scarce in normal immortalized cells, but is ubiquitous and robust in malignant cancer cells. Moreover, NT occurs in the nucleolus and requires normal nucleolar function. Intriguingly, NT is reduced by cellular stresses and anti‐tumor agents and positively correlates with cancer cell proliferation and growth. By using a modified puromycin‐associated nascent chain proteomics, we further identified numerous oncoproteins that are preferentially translated in the nucleus, such as transforming growth factor‐beta 2 (TGFB2) and nucleophosmin 1 (NMP1). Specific overexpression of TGFB2 and NMP1 messenger RNAs in the nucleus can increase their protein levels and promote tumorigenesis. These findings establish a previously unknown link between NT and malignancy and suggest that cancer cells might have adapted a mechanism of NT to support their need for rapid growth, which highlight the potential of NT in tumorigenesis and might also open up new possibilities for therapeutic targeting of cancer‐specific cellular functions.

Aberrant β-Catenin Expression and Its Association With Epithelial-Mesenchymal Transition and Clinical Outcomes of Colorectal Cancer

“…The translocation of β-catenin from the cell membrane to the cytoplasm or nucleus can initiate the activation of EMT-related proteins and pre-invasive factors [20]. Despite extensive research into the influence of β-catenin signaling on promoting EMT in both normal and pathological contexts, this present study is the first to provide evidence for the capacity of aberrantly localized β-catenin to trigger EMT in CRC tissue specimens.…”

Circular RNAs in hepatocellular carcinoma: biogenesis, function, and pathology

“…Thus, further stoichiometric analysis is required to explore these peptides' functions better. Notably, it is also of interest to determine if circRNAs could be translated in the nucleus (Zou et al, 2023b). Fifth, it is speculated that the aberrant expression of circRNAs observed in cancer might be affected by epigenetic changes.…”

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“…Intriguingly, recent evidence suggests that human cancer cells display certain atavistic features. [ 442 , 443 , 444 , 445 ] Therefore, it is of great interest to investigate the conservation and adaptation of mechanotransduction during evolution, which could definitely deepen our understanding on mechanobiology, as well as human physiology and pathology.…”