Loss of haspin suppresses cancer cell proliferation by interfering with cell cycle progression at multiple stages

Wang, Peiling; Hua, Xiangmei; Sun, Yang; Li, Hongyu; Bryner, Yuge Han; Hsung, Richard P.; Dai, Jun

doi:10.1096/fj.202100099r

Cited by 9 publications

(3 citation statements)

References 43 publications

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“…To validate these findings, we employed Haspin siRNA in 293T cells (Figure S2). Similarly, Haspin knockdown resulted in decreased H3T3ph levels without affecting H3S10ph (Figure S2b–d), which aligns with previous reports (Dai et al, 2005; Wang et al, 2021). Additionally, H3.3S31ph levels significantly decreased in Haspin siRNA treated‐293T cells, further supporting the role of Haspin in H3.3S31 phosphorylation (Figure S2e–g).…”

Section: Resultssupporting

confidence: 92%

Haspin mediates H3.3S31 phosphorylation downstream of Aurora B in mouse embryonic stem cells

Li,

Wu,

Liu

et al. 2024

Protein Science

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Histone phosphorylation is instrumental in regulating diverse cellular processes across eukaryotes. Unraveling the kinases that target specific histone sites is key to deciphering the underlying mechanisms. Among the various sites on histone tails that can undergo phosphorylation, the kinase responsible for H3.3S31 phosphorylation remained elusive. Since both H3.3S31ph and H3T3ph occur specifically during mitosis, and Haspin is the known kinase for H3T3 phosphorylation, we investigated its potential role in H3.3S31 phosphorylation. We employed CRISPR/Cas9, RNA interference, and specific small molecule inhibitors to eliminate Haspin function in various cell types. Our data consistently revealed a link between Haspin and H3.3S31ph. Furthermore, in vitro kinase assays provided evidence supporting Haspin's contribution to H3.3S31ph. Loss‐ and gain‐of‐function experiments targeting Haspin and Aurora B further suggested a hierarchical relationship. Haspin acts as a downstream kinase of Aurora B, specifically orchestrating H3.3S31 phosphorylation in mESCs. This study unveils a novel role for Haspin as a kinase in regulating H3.3S31 phosphorylation during mitosis. This discovery holds promise for expanding our understanding of the functional significance of Haspin and H3.3S31ph in mammals.

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Section: Resultssupporting

confidence: 92%

Haspin mediates H3.3S31 phosphorylation downstream of Aurora B in mouse embryonic stem cells

Li,

Wu,

Liu

et al. 2024

Protein Science

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“…Importantly, several studies have demonstrated that the expression of Haspin is significant in several cancer cells in addition to normal proliferating somatic cells [ 60 ]. Specifically, the overexpression of Haspin in breast [ 61 ], pancreas [ 62 ], skin [ 63 , 64 ], lung [ 63 , 64 ], bone [ 63 , 64 ], prostate [ 62 ], and bladder [ 65 ] was reported. By interfering with normal mitotic progression, Haspin knockdown or small molecule inhibition could stop the proliferation of cancer cells and trigger apoptosis [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents

Mostafa,

Chen,

Darwish

et al. 2024

Cancers

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Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

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“…Another haspin inhibitor, CX-6258 also impaired proliferation and generated the formation of micronuclei in melanoma cell lines [ 125 ]. In some cell lines, co-depletion of either p21 or p53 rescues the impairment in cell cycle progression caused haspin depletion [ 148 ]. Moreover, haspin elimination by CRISPR sensitizes tumor cells to VX680, an Aurora kinase B inhibitor in head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) cell lines [ 149 ].…”

Section: Targeting Nuclear Kinases Associated With Chromatin Remodeli...mentioning

confidence: 99%

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Lazo

2022

Cancers

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Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

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Loss of haspin suppresses cancer cell proliferation by interfering with cell cycle progression at multiple stages

Cited by 9 publications

References 43 publications

Haspin mediates H3.3S31 phosphorylation downstream of Aurora B in mouse embryonic stem cells

Haspin mediates H3.3S31 phosphorylation downstream of Aurora B in mouse embryonic stem cells

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

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