Biology subjects

Yu, F.-x.

Publications and source records attributed to Yu, F.-x..

3 recordsLinked to original sources

bioRxiv2023

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis

TERT reactivation occurs frequently in human malignancies. While BRAF activating mutation widely existed in cancers at various stages, TERT reactivation mainly occurs in advanced tumors. However, in vivo evidence for TERT role in cancer progression and the underlying mechanism is currently lacking. In this study, we induced TERT and/or BRAF V600E expression in mouse thyroid epithelium. TERT overexpression alone had no evident effect on tumor initiation. BRAFVE expression itself induced mediocre papillary thyroid cancer (PTC). Notably, the co-expression of BRAFVE and TERT resulted in aggressive poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome revealed that tumors from co-mutant mice were highly heterogeneous and dedifferentiation process significantly correlated with ribosomal pathways. Mechanistically, TERT boosted ribosomal RNA expression and protein synthesis. CX-5461, a rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation. Thus, TERT promotes thyroid cancer progression by inducing dedifferentiation, and ribosome biogenesis inhibition represents a potential treatment strategy for TERT-reactivated cancers. Highlights[tpltrtarr] TERT accelerated thyroid cancer dedifferentiation and metastasis in vivo [tpltrtarr]TERT regulated rRNA metabolism and MTORC1/ S6K/RPS6 activities [tpltrtarr]CX-5461 inhibited the progression of TERT-reactivated melanoma and thyroid cancer [tpltrtarr]Inhibition of rRNA induced redifferentiation of advanced thyroid cancer with TERT activation

cancer biology↗

bioRxiv2022

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a potential therapeutic target in YAP/TAZ-active cancers

Dysregulation of the Hippo tumor suppressor pathway and hyperactivation of YAP/TAZ are frequently observed in human cancers and represent promising therapeutic targets. However, strategies targeting the mammalian Hippo pathway are limited due to the lack of a well-established cell surface regulator. By combining protein interactome data and clinical data, we have identified transmembrane protein KIRREL1 as an upstream regulator of the Hippo pathway. KIRREL1 interacts with Hippo pathway components SAV1 and LATS1/2 via its intracellular C-terminal domain and promotes LATS1/2 activation by MST1/2 (Hippo kinases), in turn inhibiting YAP/TAZ activity and target gene expression. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. In mouse liver tumors driven by YAP activation, KIRREL1 protein is robustly induced. Moreover, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Finally, transgenic expression of KIRREL1 effectively blocked tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, suggesting an important role of KIRREL1 in inhibiting cancer development. Together, these findings indicate that KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway, and serves as a cell surface marker and potential drug target in cancers with YAP/TAZ dependency.

cancer biology↗

bioRxiv2020

HIV protease inhibitor Nelfinavir targets human DDI2 and potentiates proteasome inhibitor-based chemotherapy

Proteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/075572v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11e39a3org.highwire.dtl.DTLVardef@15a3032org.highwire.dtl.DTLVardef@1234bforg.highwire.dtl.DTLVardef@1452428_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗