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TBL1X: At the crossroads of transcriptional and posttranscriptional regulation

  • Author Footnotes
    ⁎ BAP and YY contributed equally to this article.
    Betsy A. Pray
    Footnotes
    ⁎ BAP and YY contributed equally to this article.
    Affiliations
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
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  • Author Footnotes
    ⁎ BAP and YY contributed equally to this article.
    Youssef Youssef
    Footnotes
    ⁎ BAP and YY contributed equally to this article.
    Affiliations
    Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH
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  • Lapo Alinari
    Correspondence
    Offprint requests to: Lapo Alinari, Division of Hematology, The Ohio State University, 410 West, 12th Avenue, 481D Wiseman Hall, Columbus, OH 43210
    Affiliations
    Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH
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  • Author Footnotes
    ⁎ BAP and YY contributed equally to this article.
Published:October 04, 2022DOI:https://doi.org/10.1016/j.exphem.2022.09.006

      Highlights

      • Transducin β-like protein 1 (TBL1X) is an adaptor protein.
      • Overexpression of TBL1X is associated with poor prognosis in many cancers.
      • TBL1X regulates oncogenic signaling transcriptionally and posttranscriptionally.
      • Tegavivint is a first-in-class small molecule targeting TBL1X.
      • Tegavivint is effective in preclinical cancer models and is clinically safe.
      Over the past 2 decades, the adaptor protein transducin β-like 1 (TBL1X) and its homolog TBL1XR1 have been shown to be upregulated in solid tumors and hematologic malignancies, and their overexpression is associated with poor clinical outcomes. Moreover, dysregulation of the TBL1 family of proteins has been implicated as a key component of oncogenic prosurvival signaling, cancer progression, and metastasis. Herein, we discuss how TBL1X and TBL1XR1 are required for the regulation of major transcriptional programs through the silencing mediator for tetanoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (NCOR)/ B cell lymphoma 6 (BCL6) complex, Wnt/β catenin, and NF-κB signaling. We outline the utilization of tegavivint (Iterion Therapeutics), a first-in-class small molecule targeting the N-terminus domain of TBL1, as a novel therapeutic strategy in preclinical models of cancer and clinically. Although most published work has focused on the transcriptional role of TBL1X, we recently showed that in diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, genetic knockdown of TBL1X and treatment with tegavivint resulted in decreased expression of critical (onco)-proteins in a posttranscriptional/β-catenin–independent manner by promoting their proteasomal degradation through a Skp1/Cul1/F-box (SCF)/TBL1X supercomplex and potentially through the regulation of protein synthesis. However, given that TBL1X controls multiple oncogenic signaling pathways in cancer, treatment with tegavivint may ultimately result in drug resistance, providing the rationale for combination strategies. Although many questions related to TBL1X function remain to be answered in lymphoma and other diseases, these data provide a growing body of evidence that TBL1X is a promising therapeutic target in oncology.
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