Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

2022

Front. Oncol.

Self Cite

Canonical histone H3.1 and variant H3.3 deposit at different sites of the chromatin via distinct histone chaperones. Histone H3.1 relies on chaperone CAF-1 to mediate replication-dependent nucleosome assembly during S-phase, while H3.3 variant is regulated and incorporated into the chromatin in a replication-independent manner through HIRA and DAXX/ATRX. Current literature suggests that dysregulated expression of histone chaperones may be implicated in tumor progression. Notably, ectopic expression of CAF-1 can promote a switch between canonical H3.1 and H3 variants in the chromatin, impair the chromatic state, lead to chromosome instability, and impact gene transcription, potentially contributing to carcinogenesis. This review focuses on the chaperone proteins of H3.1 and H3.3, including structure, regulation, as well as their oncogenic and tumor suppressive functions in tumorigenesis.

Section: Discussionmentioning

confidence: 99%

Dynamic Activity of Histone H3-Specific Chaperone Complexes in Oncogenesis

Wen

2022

Front. Oncol.

Self Cite

“…Polyadenylation of H3.1 mRNA has been shown to lead to displacement of histone variant H3.3 at active critical gene regulatory regions, causing deregulation of cancer-related genes, cell-cycle arrest, chromosome instability and cell transformation (17). These data indicate that overexpression of polyadenylated H3.1 mRNA due to SLBP depletion has potential carcinogenic effects (12,17).…”

Section: Introductionmentioning

confidence: 99%

“…Mutations or depletion of this protein can result in misprocessing of the canonical histone mRNAs, leading to expression of polyadenylated mRNA from each of the canonical histone genes (13)(14)(15). Unlike normally processed canonical histone mRNAs, polyadenylated mRNAs are relatively stable, which results in existence of canonical histone mRNAs outside of the S phase and increase in H3.1 protein level (16,17). Polyadenylation of H3.1 mRNA has been shown to lead to displacement of histone variant H3.3 at active critical gene regulatory regions, causing deregulation of cancer-related genes, cell-cycle arrest, chromosome instability and cell transformation (17).…”

Section: Introductionmentioning

confidence: 99%

“…Unlike normally processed canonical histone mRNAs, polyadenylated mRNAs are relatively stable, which results in existence of canonical histone mRNAs outside of the S phase and increase in H3.1 protein level (16,17). Polyadenylation of H3.1 mRNA has been shown to lead to displacement of histone variant H3.3 at active critical gene regulatory regions, causing deregulation of cancer-related genes, cell-cycle arrest, chromosome instability and cell transformation (17). These data indicate that overexpression of polyadenylated H3.1 mRNA due to SLBP depletion has potential carcinogenic effects (12,17).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of Stem-loop binding protein by nicotine via α7-nicotinic acetylcholine receptor and its role in nicotine-induced cell transformation

Sun

Raja

et al. 2022

Preprint

Self Cite

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nAChR (nicotinic acetylcholine receptors) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, not only CDK1 and CK2, two kinases well known for their function for SLBP phosphorylation and degradation, but also CDK2 and PI3K/AKT pathways are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.

“…; https://doi.org/10.1101/2022.03. 21.485231 doi: bioRxiv preprint level (16,17). Polyadenylation of H3.1 mRNA has been shown to lead to displacement of histone variant H3.3 at active critical gene regulatory regions, causing deregulation of cancer-related genes, cell-cycle arrest, chromosome instability and cell transformation (17).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Stem-Loop Binding Protein by Nicotine via α7-Nicotinic Acetylcholine Receptor and Its Role in Nicotine-Induced Cell Transformation

Sun

Raja

et al. 2022

Toxicological Sciences

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nicotinic acetylcholine receptors (α7-nAChR) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, PI3K/AKT pathway is activated by nicotine exposure and CK2 and probably CDK1, two kinases well known for their function for SLBP phosphorylation and degradation, are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.