FXR1: Linking cellular quiescence, immune genes and cancer

Cellular quiescence has been considered a homogeneous passive state wherein cells, in response to certain physiological stimuli, remain dormant until they are signaled to re-enter the cell cycle. However, in recent years, studies have indicated that quiescence is a heterogeneous active state with distinct gene expression profiles that might dictate the functional state of these cells and govern their transition into subsequent cell fates. Therefore, understanding these gene signatures and their underlying regulatory mechanisms is critical to explain aberrations under disease conditions. A comprehensive analysis of gene regulation in quiescence by Vasudevan et al led to the identification of the RNA binding protein FXR1 (Fragile X mental retardation syndrome related protein 1), a critical regulator of post-transcriptional gene expression in differentiation, development, and immunity. In a monocytic cell line, THP1 cultured under serum-starved conditions (>24 h), FXR1 associates with a modified microRNP complex (microRNA-protein) comprising of a target-specific miRNA (microRNA) and AGO2 (Argonaute-2 protein). This complex recruited onto the AU-rich element (ARE) of a target mRNA such as TNFa (Tumor necrosis factor alpha) resulted in enhanced translation. The mechanism of non-canonical translation in such a quiescent state is dependent on the ability of FXR1 to form FXR1/AGO2/microRNA complex that associates with a specialized translation factor, DAP5/p97 (Fig. 1). Interestingly, FXR1 is also associated with poor clinical outcomes in several cancers including NSCLC (non small cell lung cancer), ovarian, breast and HNSC (head and neck squamous cell carcinoma). This effect was attributed to its ability to regulate the expression of 2 oncogenes, protein kinase C and iota and epithelial cell transforming 2. In response to certain stimuli, cells enter a transition state where they can undergo quiescence, re-enter the cell cycle or terminally differentiate. While the role of FXR1 in quiescence has been studied, whether it can regulate mRNA levels of specific genes in this transition state and consequently alter cell function is not clear. In the current volume of Cell Cycle, Le Tonqueze O, et al analyzed the effect of FXR1 depletion on mRNA levels in THP1 cells cultured either with serum or under 24 h early serum-starved conditions representing the transition state. They showed that FXR1 regulates mRNA levels of proinflammatory (IL-1b and TNFa) and migration (CCL2 and CCL3) specific genes in the early serum starved conditions. Depletion of FXR1 in THP1 cells led to a reduction in CCL2 mRNA levels and conversely, CCL2 mRNA expression was increased upon overexpression of FXR1 in both serum-grown and early serum starved conditions. Additionally, mRNA and protein levels of IL-1b and TNFa were significantly reduced in the absence of FXR1 in early serum-starved cells (Fig. 1). IL-1b and TNFa could not be detected in serum-grown THP1 cells. The mechanism by which FXR1 increases RNA levels is not clear. Furthermore, FXR1 depletion significantly reduced cell migration of serum-starved THP1 monocytes. Thus, this paper highlights a novel function of FXR1 in regulating pro-inflammatory genes, chemokine expression, and cell migration. The specific miRNAs associated with this translational activation of proinflammatory and chemokine genes and the role of FXR1 in regulating gene expression in other cell types remains to be determined. However, studies by this group have revealed a hitherto unknown regulatory pathway that has major implications. Firstly, it suggests an unconventional role for miRNAs in upregulating gene expression under specific conditions. Since miRNAs are extensively studied as potential biomarkers and therapeutic targets, it is imperative to understand the cellular state during such analyses and its mechanism of action. Second, cancer cells are a heterogeneous population consisting of quiescent cancer stem cells (CSC) that contribute to the reactivation and recurrence of tumors. The regulation of genes that enable quiescence maintenance, resistance to therapy and re-entry into proliferation is not clearly understood. The overexpression of FXR1 in tumors and its role in maintaining translational activation in quiescent cells necessitates further exploration of this molecule in CSCs. Lastly, circulating monocytes are typically precursors of macrophages and are implicated in immune surveillance where they are recruited in response to microenvironment stimuli and elicit an inflammatory response. In this context, the role of FXR1 in dictating downstream functions needs to be elucidated. Overall, these studies lay precedent to unravel the physiological relevance of quiescence-associated networks in diseases.