BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.

PIWI-associated RNAs (piRNAs or piRs), a new-found class of small non-coding RNAs, which are mainly expressed in germline cells and partly in somatic lines, have a vital role in carcinogenesis by maintaining genomic integrity and regulation of epigenetics. The previous studies have confirmed that the expression of piR-651 is upregulated in several cancer tissue and cell lines, including lung cancer. However, the mechanism of carcinogenesis and piR-651 remains to be elucidated. Therefore, the present study assessed the 95-D high metastasis human lung cancer cell line to detect the effect of piR-651 on carcinogenesis. Firstly, piR-651 promoted the high metastasis characteristic of the 95-D cell lines by Transwell and wound-healing assays. The influence of piR-651 on tumor cell proliferation and apoptosis was detected by the MTT assay and flow cytometry. In conclusion, piR-651 may be an oncogene in lung cancer formation and development. Therefore, piR-651 regulated carcinogenesis by influencing cell proliferation, apoptosis, migration and invasion, and may be a potential tumor marker and therapeutic target.

Dysfunction and loss of the retinal pigment epithelium (RPE) are hallmarks of retinal degeneration, but the underlying pathogenetic processes are only partially understood. Using mice with a null mutation in the transcription factor gene Mitf, in which RPE deficiencies are associated with retinal degeneration, we evaluated the role of trophic factors secreted by the RPE in retinal homeostasis. In such mice, the thickness of the outer nuclear layer (ONL) is as in wild type up to postnatal day 10, but then is progressively reduced, associated with a marked increase in the number of apoptotic cells and a decline in staining for rhodopsin. We show that retinal degeneration and decrease in rhodopsin staining can be prevented partially in three different ways: first, by recombining mutant-derived postnatal retina with postnatal wild-type RPE in tissue explant cultures; second, by adding to cultured mutant retina the trophic factor pigment epithelium-derived factor (PEDF; also known as SERPINF1), which is normally produced in RPE under the control of Mitf; and third, by treating the eyes of Mitf mutant mice in vivo with drops containing a bioactive PEDF 17-mer peptide. This latter treatment also led to marked increases in a number of rod and cone genes. The results indicate that RPE-derived trophic factors, in particular PEDF, are instrumental in retinal homeostasis, and suggest that PEDF or its bioactive fragments may have therapeutic potential in RPE deficiency-associated retinal degeneration.

Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.