Figure 7. Schematic representation of the potential molecular mechanism behind metformin mediated increase in H2A. Z and dynamics in PCa.

(A) SIRT1 is overexpressed in PCa [52] (black thick arrow). Metformin treatment down-regulates the Sirt1/Pgc-1α/Nrf2 [54] and hence the levels of SIRT1 (blue arrow) which results in an increase in H2A.Z (black arrow)[55] and a restriction in tumor growth. (B) Androgen receptor (AR) is overexpressed in prostate cancer cells and up-regulates the expression of AR-dependent genes (1). During the process histone variant H2A.Z is released from promoters and enhancer regions (2) [21]. Upon metformin treatment, the occupancy of H2A.Z observed at the promoter regions and in different regions of these genes increases (3-4) and results in a reduction of their expression (5). The increase in H2A.Z particularly observed at promoter regions (3) is surprising and we suggest that this is the result of an antagonistic mechanism with androgen (6) which represses the expression of these genes (7). Hence, H2A.Z plays an important role in restricting tumor growth (8). The black arrows indicate the pathway involved in AR response and the blue arrows and triangles denote the alterations resulting from metformin treatment. Abbreviations: A, androgen; ARE, androgen responsive element.