Alternative mechanisms of miR-34a regulation in cancer

Abstract

MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.

Figure 1

Feedback regulation of miR-34a. Upon DNA damage, miR-34a transcription is induced by p53. miR-34a targets p53 directly by interaction with its transcript and indirectly through targeting of p53 inhibitor MDMX (yellow). MiR-34a-mediated inhibition of p53 deacetylase SIRT1 is implicated in apoptosis (green). Feedback inhibition between miR-34a, IL-6R and P-STAT3 is implicated in inflammation, while regulation of PD-L1 – P-Akt axis is important for immune surveillance (red). In EMT, miR-34a is implicated in multiple feedbacks encompassing EMT regulators Snail, ZEB1 or AXL (blue)

Figure 2

Reported mechanisms of p53-independent miR-34a regulation in different biological contexts. Intrinsic/intracellular mechanisms are represented in red, extrinsic mechanisms triggered by intercellular or microenvironmental effects are depicted in blue. Notably, certain molecules are characterized by context-dependent roles in the regulation of miR-34a