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