microRNA (miRNA) is a class of small non-coding RNAs that suppress the expression of protein-encoding genes via translational repression and/or mRNA degradation. Studies indicate that miRNAs act as global regulators of cellular functions, through their involvement in a wide range of physiological and pathological processes including cancer development. In a genetic screen, we found that miR-30, a miRNA frequently overexpressed in cancer, disrupts a critical tumor suppressing mechanism called oncogene-induced senescence. Further studies demonstrated that miR-30 disrupts oncogenic ras-induced senescence by directly targeting CHD7, a transcriptional co-activator, and TNRC6A, an RNA-binding protein essential for miRNA functionality. In this grant application, we will investigate te mechanisms underlying the roles of CHD7 and TNRC6A in miR-30-mediated bypass of oncogenic ras-induced senescence, and examine the impact of the miR-30-CHD7/TNRC6A regulatory circuit on cancer development in vivo.
In Aim 1, we will investigate the hypothesis that CHD7 acts as a transcriptional coactivator to induce the transcription of a key senescence effector p16INK4A, and that by suppressing CHD7, miR-30 inhibits ras-induced p16INK4A expression and hence senescence induction. Alternative approaches are proposed to perform ChIP-seq analysis to systematically identify additional direct transcriptional targets of CHD7 involved in senescence.
In Aim 2, the hypothesis will be tested that by suppressing TNRC6A, miR-30 globally down-regulates the functionality of miRNAs, which in turn leads to disruption of ras-induced senescence.
In Aim 3, we will analyze the effect of miR-30 on senescence induction and cancer development in vivo using miR-30 transgenic mice and a mouse cancer model. In addition, the expression levels of miR-30, CHD7 and TNRC6A will be determined in human tumor samples, in order to establish that miR-30 contributes to human cancer development by suppressing its direct targets CHD7 and TNRC6A. Studies proposed in this grant will provide mechanistic insights into the novel function of miR-30 in oncogene-induced senescence. Through analyses of these miR-30 targets, we will identify novel mechanisms and novel signaling components that mediate oncogene-induced senescence and tumor suppression, which will offer new opportunities for cancer therapies targeting cellular senescence.
This proposal focuses on mechanistic studies of the novel function of a microRNA (miR-30) in oncogene-induced senescence, an important fail-safe tumor suppressing defense response in mammals. Results from the proposed work will advance our knowledge about the mechanisms that protect human against cancer. The proposed studies will identify novel signaling components that mediate oncogene-induced senescence and tumor suppression, which will likely offer new opportunities for cancer therapies.
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|Jansma, Ariane L; Martinez-Yamout, Maria A; Liao, Rong et al. (2014) The high-risk HPV16 E7 oncoprotein mediates interaction between the transcriptional coactivator CBP and the retinoblastoma protein pRb. J Mol Biol 426:4030-48|