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  • PC is considered as a cancer

    2024-06-21

    PC is considered as a cancer of the epigenome (Grasso et al., 2012, Robinson et al., 2015). Our results demonstrate that the interaction of AR with ACK1 drives the positive feedback epigenetic circuitry that is ultimately conducive to promote AR transcription. Further, this circuitry subjugates AR transcription in CRPCs when the H4-Y88 epigenetic regulation is terminated. An unexpected finding that has emerged from this study is the role of ACK1 as an “epigenetic writer” that deposits the first layer of pY88-H4 marks, which are recognized by an “epigenetic reader” WDR5. This, in turn, results in the recruitment of the WDR5 partner MLL2, which acts as the “epigenetic scribe” and introduces H3K4me3-activating marks to drive AR expression. Interestingly, recent studies have shown that AR interacts with menin, which is a component of the MLL1/WDR5/ASH2L complex (Grasso et al., 2012, Malik et al., 2015). Whether H4 Y88phosphorylation was important for the assembly of MLL1/WDR5/menin complex is not known; however, the presence of WDR5 in both MLL1 and MLL2 complexes does not rule out the possibility of the global regulatory function of pY88-H4 marks in regulation of the AR target genes. Significantly, our proteomics analysis revealed many other WD repeat-containing proteins, including WDR55, WDR43, WDR19, WDR12, WDR46, and WDR75, also binding to pY88-H4, opening the possibility that WD40 repeat could be the pY88-H4 reader element and that WD40 repeat-containing proteins might be recruited to mibefradil using these epigenetic marks. In addition to WDR5, our assessment of pY88-H4 ChIP-seq peaks revealed the top match being the SOX8 (or sex determining region Y-box 8), a transcription factor involved in the regulation of embryonic development and determination of the cell fate, including male sex determination (Chaboissier et al., 2004). Whether pY88-H4 marks have an additional role in male gonad differentiation remains to be seen. Prompt restoration of AR expression reinforces the notion that sustained androgen deprivation may prompt CRPC tumors to use ACK1/pY88-H4 epigenetic signaling to overcome androgen dependence. Although ACK1/pY88-H4/AR signaling could be the promising scheme for CRPCs to acquire the above-mentioned properties; the unavailability of an ACK1 small-molecule inhibitor precluded testing this hypothesis comprehensively. Our data not only provide evidence of CRPC dependence on ACK1-AR signaling, but also indicates that enzalutamide-non-responsive PCs may be sensitive to the ACK1 inhibitor. Indeed, combining enzalutamide with (R)-9bMS might provide the best outcome, dampening the progression of early disease to castration resistance. Overall, uncovering the epigenetic control of CRPCs has considerable potential to advance (R)-9bMS as a therapeutic option.
    STAR★Methods
    Author Contributions
    Introduction Tyrosine kinases are being pursued as effective targets in cancer therapy due to the strident dependence of cancer cells on one or more these entities for proliferation and survival. At least 90 unique tyrosine kinases are encoded by the human genome, of which 58 comprise the receptor-tyrosine kinases (RTKs)-grouped into 20 subfamilies, and 32 non-receptor tyrosine kinases (NRTKs) categorized into 10 subfamilies based on structure of the kinase domain [1], [2]. In addition, there are some unusual members such as the WSTF (Williams–Beuren Syndrome Transcription Factor), which tyrosine phosphorylates the variant histone, H2AX in the chromatin [3]. Since the first clinical success of tyrosine kinase inhibitor (TKI), Imatinib or Gleevec, against BCR-ABL in chronic myeloid leukemia (CML), at least fifteen other TKIs have been evaluated in clinical setting [4], [5]. Notable are the TKIs targeting HER2/Neu, EGFR, VEGF and B-Raf [6], [7], [8], [9], [10]. Consequently, selective targeting of the deregulated oncogenic kinases-HER2 with Trastuzumab in ‘HER2-positive’ breast cancers and the mutant B-RafV600E with Vemurafenib (PLX-4032) in melanomas causes significant tumor regression. However, this personalized therapy approach is advantageous only when patients with a specific addictive oncogene have been identified and specific inhibitors are available. With the emergence of large scale sequencing platforms and various gene-profiling methodologies, identification of kinases that promote cancer cell survival, proliferation and metastasis is principally streamlined. In this review, we summarize the latest developments in elucidating the biochemical and pathological role of an understudied tyrosine kinase, ACK1, in cancer cell survival and discuss novel small molecular inhibitors in terms of their suitability for targeting ACK1 in different cancer types (see Table 1, Table 2).