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

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/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

Cell Death Discovery ◽

10.1038/s41420-021-00402-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yu Wang ◽

Liming Zhu ◽

Mei Guo ◽

Gang Sun ◽

Kun Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cell ◽

Cell Apoptosis ◽

B Cell Lymphoma ◽

Histone Methyltransferase ◽

Chemotherapeutic Agents ◽

Cancer Cell Apoptosis ◽

Active Transcription

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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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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Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01882-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Zizhen Si ◽

Lei Yu ◽

Haoyu Jing ◽

Lun Wu ◽

Xidi Wang

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Xenograft Model ◽

Luciferase Reporter ◽

Cancer Proliferation ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

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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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LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1

10.21203/rs.3.rs-35112/v1 ◽

2020 ◽

Author(s):

Peng Shen ◽

Lili Qu ◽

Jingjing Wang ◽

Quchen Ding ◽

Chuanwen Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Xenograft Model ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Protein Coding ◽

Mechanistic Investigation ◽

Rna Immunoprecipitation

Abstract Background Long intergenic non-protein coding RNA 342 (LINC00342) has been identified as a novel oncogene, however, the functional role of LINC00342 in colorectal cancer (CRC) remained unclear. Methods The expression of LINC00342 was detected by real-time PCR. Cell proliferation, migration and invasion and xenograft model were examined to analyze the biological functions of LINC00342 in vitro and in vivo. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to identify the target interactions between LINC00342, miR-19a-3p and aminopeptidase like 1 (NPEPL1). Results LINC00342 was highly expressed in CRC. Downregulation of LINC00342 inhibited cell proliferation and metastasis of CRC cells. Moreover, knocking down LINC00342 could weaken the tumor growth in vivo. Mechanistic investigation revealed that LINC00342 may sponge miR-19a-3p to regulate NPEPL1 expression. Further investigation indicated that the oncogenesis facilitated by LINC00342 was inhibited by NPEPL1 depletion.Conclusion LINC00342 promoted CRC progression by competitively binding miR-19a-3p with NPEPL1.

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LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1 axis

Cancer Cell International ◽

10.1186/s12935-020-01705-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Peng Shen ◽

Lili Qu ◽

Jingjing Wang ◽

Quchen Ding ◽

Chuanwen Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Xenograft Model ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Pcr Analysis ◽

Protein Coding ◽

Mechanistic Investigation

Abstract Background Long intergenic non-protein coding RNA 00342 (LINC00342) has been identified as a novel oncogene. However, the functional role of LINC00342 in colorectal cancer (CRC) remains unclear. Methods The expression of LINC00342 is detected by real-time PCR (RT-PCR) analysis. Cell proliferation, migration and invasion and xenograft model are examined to analyze the biological functions of LINC00342 in vitro and in vivo using colony formation, would healing and transwell analyses. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays are used to identify the target interactions between LINC00342, miR-19a-3p and aminopeptidase like 1 (NPEPL1). Results LINC00342 was highly expressed in CRC. Down-regulation of LINC00342 inhibited cell proliferation and metastasis of CRC cells. Moreover, knocking down LINC00342 inhibited the tumor growth in vivo. Mechanistic investigation revealed that LINC00342 might sponge miR-19a-3p to regulate NPEPL1 expression. Further investigation indicated that the ontogenesis facilitated by LINC00342 was inhibited due to the depletion of NPEPL1. Conclusion LINC00342 promotes CRC progression by competitively binding miR-19a-3p with NPEPL1.

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