Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer

Abstract

Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16(INK4a) protein, has a causal link with several different types of cancers. The p16(INK4a) protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK) 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.

Keywords: CDKN2A; Cancer; Epigenetic alterations; Genetic alterations; p16(INK4a).

Fig. 1

Schematic structure of the INK4a/ARF locus and the role of p16^INK4a in cells. CDKN2A is produced by alternative splicing of E1, E2 and E3. The p16^INK4a protein binds to the cyclin D and CDK4/6 complexes and inhibits the activation of the transcription factor, E2F1, which induces proteins to move from the G1 phase to S phase in the cell cycle.

Fig. 2

Frequency of CDKN2A alterations in various cancer types. Based on the types of aberrant CDKN2A, the bars represent the percentage of changes reported.

Fig. 3

The epigenetic induction of p16^INK4a by regulatory genes. FOXA1, Si-ZBP-89, Jmjd3, Mutant UHRF1 and c-JUN induce p16^INK4a protein expression by re-activation of the CDKN2A promoter.

Fig. 4

The epigenetic induction of p16^INK4a by reagents. Phytochemicals such as genistein, SFN and EGCG and synthetic chemicals, TSA, 5-aza-2′-deoxycytidine, irinotecan, cladribine, clofarabine, doxorubicin, FUMI (5-fluorouracil + mitomycin C) and combinations reactivate p16^INK4a protein expression by prohibiting alterations in the CDKN2A promoter.