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  • FOX proteins constitute a large class of


    FOX proteins constitute a large class of transcription factors with multiple functions, from development and organogenesis to regulation of metabolic and immune functions. The Fox transcription factor is characterized by a 100-amino-acid wing helix or forkhead DNA-binding domain. In addition, the FOX protein subfamily, including FOXP1-P4, contains a zinc finger domain and a leucine zipper motif and can act as a transcriptional repressor by forming homo- or heterodimers with other family members. The function of FOXP1 has been widely studied in blood, lung, heart, and immune cells.41, 42, 43 Other studies have shown that FOXP1 can act as an oncogene in diffuse large B cell lymphoma and mucosa-associated lymphoid tissue lymphoma or can act as a tumor suppressor in gastrointestinal, lung, genitourinary, and breast cancers. In the present study, FOXP1 is found to be responsible for the attenuation of cyclin E2 expression by miR-3687i at the transcriptional level. FOXP1 can transcriptionally inhibit the transcription of cyclin E2, indicating that FOXP1 acts as a tumor suppressor in BC cells, an effect that has not been reported in previous studies. In summary, the current study showed for the first time that miR-3687 is upregulated in BC tissue and cell lines. Functional studies revealed that miR-3687 promotes BC cell growth in vitro and tumor formation in vivo and downregulates FOXP1 expression (by targeting its 3′ UTR). Subsequent reduction of FOXP1 promotes the transcription of cyclin E2 by decreasing its binding to the cyclin E2 promoter. Eventually, increased levels of cyclin E2 promote BC cell proliferation through promoting the G0/G1 transition. Taken together, these results indicate that miR-3687 is a critical cancer-promoting molecule in BC and that miR-3687 and its downstream effectors may serve as potential targets for early diagnosis and/or as targets for treatment of BC patients.
    Materials and Methods
    Author Contributions
    Conflicts of Interest
    Acknowledgments The results published here are entirely based on data generated by the TCGA Research Network ( We thank the participants, specimen donors, and research groups who developed the TCGA JTP-74057 cancer dataset resource for their contributions to database construction, and we also thank Eryun Information Technology Co., Ltd. (Shanghai, China), for assisting us in analyzing the data. This work was partially supported by the Natural Science Foundation of China (NSFC81601849, NSFC81872587 and NSFC81702530); Wenzhou Science and Technology Bureau (Y20170028, Y20160075, and Y20180109); Zhejiang Medical and Health Science and Technology Project (2019326532); Key Discipline of Zhejiang Province in Medical JTP-74057 Technology (First Class, Category A); and the Key Project of Science and Technology Innovation Team of Zhejiang Province (2013TD10).
    Introduction Ubiquitination of proteins regulates myriads of cellular processes including proteostasis, localization, and DNA repair [1]. Ubiquitin-activating enzyme (E1) initiates the process by activating the ubiquitin (Ub) in an ATP-dependent manner and subsequently transfers the activated Ub to a conjugating E2 enzyme via trans-thio-esterification reaction. Finally, an E3 ligase transfers Ub from an E2~Ub conjugate to a free amino group on a substrate protein, either directly (RING/U-box E3 ligases) [2] or via its own active-site residue (HECT/RBR E3 ligases) [3], [4]. Diverse consequences of ubiquitination arise from modifications of various substrates and their modification topology. Substrates can be modified by the addition of either one Ub (mono-ubiquitination) or Ub chains (poly-ubiquitination) formed through one of its seven lysine residues or the amino-terminus [5], [6]. Mono-ubiquitination of substrates has been implicated in non-degradative processes such as transcription regulation [7], [8] and cellular localization [9]. In contrast, poly-ubiquitination, depending on the chain type, may lead to either degradation of the substrate or activation of downstream pathways including NFκB-mediated transcription activation [10], [11] and error-free DNA repair [12]. The ubiquitination machinery, therefore, needs to maintain specificity in substrate recognition and modification topology. E3 ligases confer the former by their selective interaction with the substrates. E2s, on the other hand, dictate the topology of modification. For example, Ube2S exclusively synthesizes Lys11-linked Ub chains [13] and Ube2N in complex with the E2 variant Ube2V1 modifies the substrate via Lys63-linked chains [14]. E3s also contribute in deciding the ubiquitination topology by recruiting the necessary E2 or by altering the E2 functionality [15]. Thus, an E3, in conjunction with its E2 partners, warrants the precise biological response that ensues.