Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2025
[PINK1 suppresses colorectal cancer cell growth through epigenetic regulation of histone modifications].
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Wang Meng, Luan Shijia, Fan Xiang, Han Dong, Zhu Yuping
Аннотация
OBJECTIVES: To investigate the role of PTEN-induced putative kinase 1 (PINK1) in regulating the viability, migration, and apoptosis of colorectal cancer (CRC) cells, and to explore its potential epigenetic mechanisms.
METHODS: PINK1 was overex-pressed or knocked down in HCT116 and DLD1 CRC cell lines using lentiviral vectors, with efficiency verified by qRT-PCR and Western blotting. Cell proliferation was assessed using CCK-8 and colony formation. Cell migration was detected using wound healing and Transwell assays. Apoptosis was assessed using Hoechst 33258 staining. Protein levels of apoptosis-related and histone modification-related markers were analyzed by Western blotting. Genome-wide chromatin accessibility was profiled using assay for transposase-accessible chromatin with sequencing (ATAC-seq).
RESULTS: PINK1 expression was significantly downregulated at both mRNA and protein levels in CRC tissues com-pared to normal tissues. PINK1 overexpression inhibited cell proliferation, colony formation, and migration in HCT116 and DLD1 cells (all P<0.05), whereas PINK1 knockdown promoted these malignant phenotypes (all P<0.05). PINK1 overexpression induced apoptosis, associated with decreased levels of anti-apoptotic proteins (MCL-1, BCL-2, BCL-XL) and increased pro-apoptotic BAX (all P<0.05), without altering p53 expression. Mechanistically, PINK1 overexpression reduced histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 27 trimethylation (H3K27me3), and increased histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 27 acetylation (H3K27ac). It also downregulated key histone-modifying enzymes, including enhancer of Zeste homolog (EZH)2, EZH1, SUZ12, and histone deacetylase 3 (HDAC3) (all P<0.01). ATAC-seq revealed that PINK1 overexpression increased chromatin accessibility, particularly around transcription start sites.
CONCLUSIONS: PINK1 acts as a tumor suppressor in colorectal cancer by inhibiting proliferation and migration, promoting apoptosis, and remodeling the epigenetic landscape through altering histone modifications and enhancing chromatin accessibility.
METHODS: PINK1 was overex-pressed or knocked down in HCT116 and DLD1 CRC cell lines using lentiviral vectors, with efficiency verified by qRT-PCR and Western blotting. Cell proliferation was assessed using CCK-8 and colony formation. Cell migration was detected using wound healing and Transwell assays. Apoptosis was assessed using Hoechst 33258 staining. Protein levels of apoptosis-related and histone modification-related markers were analyzed by Western blotting. Genome-wide chromatin accessibility was profiled using assay for transposase-accessible chromatin with sequencing (ATAC-seq).
RESULTS: PINK1 expression was significantly downregulated at both mRNA and protein levels in CRC tissues com-pared to normal tissues. PINK1 overexpression inhibited cell proliferation, colony formation, and migration in HCT116 and DLD1 cells (all P<0.05), whereas PINK1 knockdown promoted these malignant phenotypes (all P<0.05). PINK1 overexpression induced apoptosis, associated with decreased levels of anti-apoptotic proteins (MCL-1, BCL-2, BCL-XL) and increased pro-apoptotic BAX (all P<0.05), without altering p53 expression. Mechanistically, PINK1 overexpression reduced histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 27 trimethylation (H3K27me3), and increased histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 27 acetylation (H3K27ac). It also downregulated key histone-modifying enzymes, including enhancer of Zeste homolog (EZH)2, EZH1, SUZ12, and histone deacetylase 3 (HDAC3) (all P<0.01). ATAC-seq revealed that PINK1 overexpression increased chromatin accessibility, particularly around transcription start sites.
CONCLUSIONS: PINK1 acts as a tumor suppressor in colorectal cancer by inhibiting proliferation and migration, promoting apoptosis, and remodeling the epigenetic landscape through altering histone modifications and enhancing chromatin accessibility.