Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2

AbstractWHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in CRC patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

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Histone Methyltransferase WHSC1 Inhibits Colorectal Cancer Cell Apoptosis via Targeting Anti-apoptotic BCL2

10.21203/rs.3.rs-35111/v2 ◽

2020 ◽

Author(s):

Yu Wang ◽

Xin Tang ◽

Mei Guo ◽

Gang Sun ◽

Kun Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cell ◽

Cell Apoptosis ◽

Xenograft Model ◽

Histone Methyltransferase ◽

Cancer Cell Apoptosis ◽

Mechanistic Investigation

Abstract Background: WHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. Colorectal cancer (CRC) is the 4th deadliest and 3rd most frequent cancer globally. However, the role of WHSC1 in CRC progression remains unknown. Methods: qRT-PCR, immunoblotting assays (WB), and immunohistochemistry (IHC) staining was performed to investigate WHSC1 expression levels in CRC tissues and normal tissues. CCK-8 assays, colony formation assays, and flow cytometry were also used to assess the effect of WHSC1 depletion in CRC cell proliferation, apoptosis and oxaliplatin sensitivity in vitro. A cell line-derived xenograft model in nude mice was performed to determine the role of WHSC1 in CRC cell apoptosis in vivo. Results: WHSC1 as well as H3K36me2 were highly expressed in clinical CRC tissues compared with in normal counterparts. High WHSC1 expression was correlated with poorer prognosis in CRC patients. Knockdown of WHSC1 significantly promoted CRC cell apoptosis and inhibited tumour growth in vivo. Further mechanistic investigation revealed that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level, so BCL2 expression is markedly decreased after WHSC1 depletion. Conclusions: Our findings demonstrated that knockdown of WHSC1 promoted colon cancer cell apoptosis and suppressed CRC tumorigenesis through targeting BCL2 transcription, suggesting WHSC1 activity may be a potential therapeutic target for the treatment of CRC.

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Histone Methyltransferase WHSC1 Inhibits Colorectal Cancer Cell Apoptosis via Targeting Anti-apoptotic BCL2

10.21203/rs.3.rs-35111/v1 ◽

2020 ◽

Author(s):

Yu Wang ◽

Xin Tang ◽

Mei Guo ◽

Gang Sun ◽

Kun Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cell ◽

Cell Apoptosis ◽

Xenograft Model ◽

Histone Methyltransferase ◽

Cancer Cell Apoptosis ◽

Mechanistic Investigation

Abstract Background: WHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. Colorectal cancer (CRC) is the 4th deadliest and 3rd most frequent cancer globally. However, the role of WHSC1 in CRC progression remains unknown.Methods: qRT-PCR, immunoblotting assays (WB), and immunohistochemistry (IHC) staining was performed to investigate WHSC1 expression levels in CRC tissues and normal tissues. CCK-8 assays, colony formation assays, and flow cytometry were also used to assess the effect of WHSC1 depletion in CRC cell proliferation, apoptosis and oxaliplatin sensitivity in vitro. A cell line-derived xenograft model in nude mice was performed to determine the role of WHSC1 in CRC cell apoptosis in vivo.Results: WHSC1 as well as H3K36me2 were highly expressed in clinical CRC tissues compared with in normal counterparts. High WHSC1 expression was correlated with poorer prognosis in CRC patients. Knockdown of WHSC1 significantly promoted CRC cell apoptosis and inhibited tumour growth in vivo. Further mechanistic investigation revealed that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level, so BCL2 expression is markedly decreased after WHSC1 depletion.Conclusions: Our findings demonstrated that knockdown of WHSC1 promoted colon cancer cell apoptosis and suppressed CRC tumorigenesis through targeting BCL2 transcription, suggesting WHSC1 activity may be a potential therapeutic target for the treatment of CRC.

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The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo

Cancer Letters ◽

10.1016/j.canlet.2014.08.009 ◽

2014 ◽

Vol 354 (1) ◽

pp. 189-199 ◽

Cited By ~ 42

Author(s):

Kaiyan Hui ◽

Yang Yang ◽

Kejian Shi ◽

Hui Luo ◽

Jing Duan ◽

...

Keyword(s):

Colorectal Cancer ◽

P38 Mapk ◽

Cancer Cell ◽

Cell Apoptosis ◽

Colorectal Cancer Cell ◽

Cancer Cell Apoptosis

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Anticancer Effects of Cyclocarya paliurus Polysaccharide (CPP) on Thyroid Carcinoma In Vitro and In Vivo

International Journal of Polymer Science ◽

10.1155/2018/2768120 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Zhiwei He ◽

Fangfang Lv ◽

Yueli Gan ◽

Jing Gu ◽

Ting Que

Keyword(s):

Thyroid Cancer ◽

Cancer Cell ◽

Western Blotting ◽

Cell Apoptosis ◽

Cancer Cell Line ◽

B Cell Lymphoma ◽

Thyroid Cancer Cell ◽

Cyclocarya Paliurus

In this study, we explored the role and mechanisms of Cyclocarya paliurus polysaccharide on cell apoptosis in thyroid cancer (TC) cells. The apoptosis of thyroid cancer cells in vitro and tumor tissues in vivo induced by Cyclocarya paliurus polysaccharide was determined by MTT assay and flow cytometric assay. The downstream molecules including phosphop-protein kinase B (p-Akt), Akt, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) in tumor tissue were evaluated by western blotting. MTT and flow cytometry assay in vitro revealed Cyclocarya paliurus polysaccharide-induced apoptosis of thyroid cancer cell line in a manner of time-dependent and dose-dependent. In vivo assay showed 50 mg/kg and 100 mg/kg Cyclocarya paliurus polysaccharide significantly suppressed the proliferation of thyroid cancer in mice. Western blotting showed downregulation of p-Akt, Akt, and Bcl-2 and upregulation of Bax. These results suggest that Cyclocarya paliurus polysaccharide may enhance thyroid cancer cell apoptosis by suppressing the activation of p-Akt, Akt, and Bcl-2 and activating Bax, which provide a novel use of CPP as a thyroid cancer treatment.

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Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

Molecular Biology of the Cell ◽

10.1091/mbc.e14-10-1438 ◽

2015 ◽

Vol 26 (6) ◽

pp. 1044-1057 ◽

Cited By ~ 10

Author(s):

Chen Wei ◽

Ma Lin ◽

Bian Jinjun ◽

Feng Su ◽

Cao Dan ◽

...

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Protein Level ◽

Cell Apoptosis ◽

General Control ◽

Screening Assay ◽

Cancer Cell Apoptosis ◽

Cancer Cell Death

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.

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