PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer

Abstract

Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy.

Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders

“…For example, MORC ATPases have been shown to be involved in heterochromatin silencing in eukaryotes [66] and following DNA damage, MORC2 can facilitate chromatin remodeling and promote gamma-H2AX induction [67]. As another example, PHF2 is a tumor suppressor that is required for the anticancer effects of doxorubicin in cell lines with active p53 [68]. Finally, CBX8 is part of the polycomb repressive complex 1 (PRC1) [69] involved in the transition from a polycomb-repressed to active chromatin state during ES cell differentiation [70].…”

Implication of PHF2 Expression in Clear Cell Renal Cell Carcinoma

“…A recent study showed that PHF2 can modulate p53 by demethylating H3K9me2, and down-regulation of PHF2 expression occurs in colon and stomach cancer [16]. In the study, they suggested that PHF2 acts as a tumor suppressor by regulating the function of p53 [16].…”

“…To the best of our knowledge, only a few studies have investigated the association of PHF2 expression with human cancers, such as breast cancer, esophageal cancer and squamous cell carcinoma of the head and neck [13-15]. A recent study has shown that PHF2 can act as a tumor suppressor through epigenetic regulation of p53 and shows reduced expression in colon cancer and stomach cancer tissues [16]. However, there has been no report of PHF2 expression in CCRCC.…”

Advances in the development of histone lysine demethylase inhibitors

“…PHF8 is required for normal development and mutations in the gene cause X-linked mental retardation, but elevated expression of PHF8 has also been shown to be oncogenic in solid cancer [15,16]. PHF2, on the contrary, has been described as a potential tumor suppressor [17,18]. …”