TBL1X: At the crossroads of transcriptional and posttranscriptional regulation.
TBL1X: At the crossroads of transcriptional and posttranscriptional regulation.
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DOI：
10.1016/j.exphem.2022.09.006
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发表时间：
2022-12
影响因子：
2.6
通讯作者：
Alinari, Lapo
中科院分区：
文献类型：
--
作者：
Pray, Betsy A.;Youssef, Youssef;Alinari, Lapo
Over the past two decades, the adaptor protein transducin beta-like 1 (TBL1X) and its homologous TBL1XR1 have been shown to be upregulated in solid tumors and hematologic malignancies and their overexpression associated with poor clinical outcome. Moreover, dysregulation of the TBL1 family of proteins has been implicated as a key component of oncogenic pro-survival signaling, cancer progression, and metastasis. Herein, we discuss how TBL1X (and TBL1XR1) are required for the regulation of major transcriptional programs through the SMRT/NCOR/BCL6 complex, Wnt/β catenin and NF-kB 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. While most of the published work focuses on TBL1X transcriptional role, 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 the decreased expression of critical (onco)-proteins in a post transcriptional/β catenin independent manner by promoting their proteasomal degradation through a Skp1/Cul1/F-Box (SCF)/TBL1X super-complex and potentially through the regulation of protein synthesis. However, given that TBL1X controls multiple oncogenic signaling pathways in cancer, treatment with tegavivint may ultimately results in drug resistance providing rationale for combination strategies. While 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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