Abstract
Heterochromatin protein 1γ (CBX3) links histone methylation marks to transcriptional silence, DNA repair and RNA splicing, but a role for CBX3 in cancer remains largely unknown. In this study, we show that CBX3 in colon cancer cells promotes the progression of the cell cycle and proliferation in vitro and in vivo. Cell cycle (G1 phase to S phase) related gene CDK6 and p21 were further identified as targets of CBX3. In addition, we found that enhancing CDK6 suppresses cell proliferation by upregulating inhibitor p21 in the absence of CBX3, and this function is independent of the kinase activity of CDK6. Our results demonstrate a key role of CBX3 in colon carcinogenesis via suppressing the expression of CDK6/p21, which may disrupt the role of CDK6 in transcriptionally regulating p21, as part of a negative feedback loop to limit CDK6 excessive activation.
Highlights
The histone proteins as well as several other proteins are essential elements of heterochromatin formation, and are associated with gene transcriptional repression or silencing [1]
To further confirm that CBX3 promotes colon cancer progression via regulating the expression of CDK6/p21, we examined the expression of CBX3, CDK6 and p21 in human non-cancerous tissue (NCA) and cancerous tissue (CA)
CBX3, from the heterochromatin protein 1 family, whose members are closely related to the biological processes in cells and have been proposed to be driving www.impactjournals.com/oncotarget forces for some diseases when they are frequently expressed at aberrant levels
Summary
The histone proteins as well as several other proteins are essential elements of heterochromatin formation, and are associated with gene transcriptional repression or silencing [1]. Dynamic CBX3 binding to H3K9 is dependent on the histone methyltransferase Suv339H1 and maintains stable heterochromatin domains to regulate gene expression [4]. CBX3 can recruit various cofactors which perform functions in intracellular biological processes by binding methylated H3K9. These functions include RNA alternative splicing, DNA damage response, transcription elongation, cell growth and differentiation [5,6,7,8,9,10]. Gene expression assays have revealed that CBX3 is linked with lung cancer, osteosarcoma, gastric cardia adenocarcinoma and colorectal cancer, among other diseases [11,12,13,14,15], the specific mechanisms by which CBX3 promotes cancer progression are poorly understood
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