Biology subjects

Liu, B. H.

Publications and source records attributed to Liu, B. H..

3 recordsLinked to original sources

bioRxiv2024

Targeting transcription factors through an IMiD independent zinc finger domain

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing an in silico docking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/574032v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@b8e4e8org.highwire.dtl.DTLVardef@bc6f01org.highwire.dtl.DTLVardef@11bbe85org.highwire.dtl.DTLVardef@791cb1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

SALL4B, not targeted by IMiD, is important for SALL4-mediated tumorigenesis

Immunomodulatory (IMiD) drugs have shown a prominent therapeutic activity in hematologic malignancies; however, their usage in solid tumors is limited. The oncofetal protein SALL4 is essential for cancer cell survival. While IMiDs can induce SALL4 degradation, they fail to induce cell death in SALL4-expressing cancer cell lines. Here, we observed that this inefficacy arose from their selective degradation of the long SALL4 isoform, while sparing the short SALL4B isoform. Selective silencing of SALL4B phenocopied total SALL4 depletion by inducing cancer apoptosis, underscoring the critical role of SALL4B in cancer maintenance. Recognizing that IMiDs cant degrade SALL4B, we performed a high-throughput screen to identify compound(s) that could achieve this. We identified a small molecule compound that degrades both SALL4 isoforms with enhanced potency towards SALL4B in a cereblon- and proteasome-dependent manner. This compound suppressed cancer cell proliferation and attenuated tumor development in both cell line and patient-derived xenograft models. Transcriptomic analyses further revealed convergent effects of genetic and pharmacologic SALL4B depletion on DNA damage response and replication pathways. Together, these findings identify SALL4B as the therapeutically relevant isoform in SALL4-dependent cancers and establish isoform-aware targeted degradation as a strategy to overcome the limitation of IMiDs in solid tumors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/548071v2_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@99670dorg.highwire.dtl.DTLVardef@13ca58forg.highwire.dtl.DTLVardef@998e7eorg.highwire.dtl.DTLVardef@15a1875_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract | Identification of QE: a non-IMiDs degrader capable of degrading both SALL4A and SALL4B, triggers anti-cancer effects beyond IMiDs, and Impacts of QE on Key Validated SALL4B Targets and Pathways C_FIG

cancer biology↗

bioRxiv2023

How formate dehydrogenase-lacking acetogen Clostridium bovifaecis utilize formate as the sole carbon source for its acetogenic growth?

Little is known about the growth of formate dehydrogenase-lacking acetogen on formate as sole carbon source. Here, we analyzed formate metabolism in Clostridium bovifaecis strain BXX using different concentrations of formate. The results show that C. bovifaecis converted formate (11.5-96 mM) into acetate with molar ratio of 2.0:1[~]2.6:1 by using L-cysteine in the anaerobic medium as electron source according to the stoichiometry of acetogenesis. Genome analysis of C. bovifaecis revealed genes encoding anaerobic ribonucleoside triphosphate reductase (nrdD and nrdG) catalyzing the oxidation of formate to CO2 while ATP is being reduced to the desoxy form. The existence of nrdD was verified by PCR, reverse transcription-PCR analysis and acetogenesis from formate. The process mode of acetogenesis from formate in C. bovifaecis provides insight into the unique metabolic feature of an FDH-lacking acetogen. IMPORTANCEWood-Ljungdahl pathway (WLP) lacking formate dehydrogenase (FDH) which catalyzes CO2 reduction to formate has been reported to occur acetogenesis only in the presence of formate and exogenous CO2, which seems to result from the formate-rich habitats adaptation of gastrointestinal acetogens. Here, we found FDH-lacking Clostridium bovifaecis strain BXX converted formate (11.5-96 mM) into acetate with molar ratio of 2.0:1[~]2.6:1 fitting the stoichiometry of acetogenesis when using formate as the sole carbon source. CO2 needed in the carbonyl branch of WLP was from the oxidation of formate to CO2 catalyzed by anaerobic ribonucleoside triphosphate reductase while ATP is being reduced to the desoxy form. L-cysteine in the anaerobic medium was the electron source of WLP. The process mode of acetogenesis from formate in C. bovifaecis provides insight into how an FDH-lacking acetogen can make a living from the simplest resources as carbon source, which has both ecological and biotechnological significance.

microbiology↗