Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications

Abstract

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-polycomb functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the polycomb-repressive and non-polycomb functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy.

Prognostic Value of Combined Immunohistochemical Expression of Bmi1 and Ezh2 in Astrocytoma

“…Abnormal PcG expression or mutations falsely activate proto-oncogenes, resulting in loss of cell character, with sustained ability of proliferation, resistance to apoptosis mechanisms, and escape of cellular senescence programs, increased migratory and invasive ability, cancer stem cells maintenance and generation [7]. Numerous PcG proteins reveal diverse expression in malignant tissue in comparison to conforming non neoplastic tissue [8]. Not only abnormal levels of PcG proteins are found in human cancers but also many missense mutations and chromosomal translocations [9].…”

“…BMI1 inhibits Mycinduced apoptosis by suppression of the cyclindependent kinase inhibitor locus, encoding ARF and INK4 proteins, both of limit proliferation of cells in response to abnormal mitogenic signaling [13]. BMI1 overexpression expects poor prognosis and advanced disease in numerous human cancers [8]. The expression of BMI1 is frequently linked to aggressive and stem cell-like chemoresistant cancers as prostate cancer [14] , head and neck cancer [15] , pancreatic adenocarcinoma [16] .…”

“…The expression of BMI1 is frequently linked to aggressive and stem cell-like chemoresistant cancers as prostate cancer [14] , head and neck cancer [15] , pancreatic adenocarcinoma [16] . However, BMI1 overexpression may not associated with a poor prognosis for all types of cancer, as BMI1 high expression are related to a improved survival in breast cancer, malignant melanoma and endometrial carcinomas patients [8]. BMI1 high expression predicts metastases in precancerous tissues and biopsies, thus acting as an invaluable diagnostic tool as in precancerous gastrointestinal tract lesions [17] .…”

“…In renal carcinoma, BMI1 expression is correlated inversely with carcinoma grade, acting as a marker of differentiation, which is lost in carcinomas of high grade [19]. BMI1, regarding progression of cancer, depends on the type of tumor cell so it necessity to be considered when developing targeted new plans for therapy [8].…”

“…EZH2 is expressed in a many human cancers, associating with tumor aggressiveness through all types of cancer [8]. EZH2 is upregulated in multiple cancers including breast [21] , and human prostate cancer, especially hormone-refractory prostate cancers [22].…”