PAF1 (PAF1 Homolog, Paf1/RNA Polymerase II Complex Component)

Here, we investigated the therapeutic efficacy of RK-33, a small molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhances the therapeutic efficacy in KRAS-driven PDAC. Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating the aggressiveness of PDAC. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.

Elevated expression of CPSF73 is associated with aggressive disease in prostate cancer patients, and combining JTE-607 with adavosertib synergistically reduced prostate cancer cell survival. Our findings suggest that transcription termination helps prevent toxic conflicts between transcription and replication following increased replication initiation caused by WEE1 inhibition.

Using these drug-resistance alleles of PAF1 to construct isogenic models, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL/AF9 antagonists.

Furthermore, CD44v6-interfering peptides effectively abrogated the growth and metastasis of established MEN1 deficient tumors by activating ferroptosis. Collectively, this study unveils a mechanism of tumor suppression based on MEN1 regulation of CD44 alternative splicing, ROS production, and ferroptosis induction.

Using these drug-resistance alleles of PAF1 to construct isogenic models, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL antagonists.

Mechanistically, BAP18 recruits ACTL6A and PAF1 to Wnt target gene promoters, enhancing β-catenin-mediated transcription. These findings suggest that BAP18 plays a critical role in NSCLC progression through the Wnt/β-catenin pathway and could serve as a novel therapeutic target, particularly for patients with Wnt/β-catenin-driven tumors.

Our findings suggest that CDX1/2 cooperatively suppressed colonic tumorigenesis and cancer stemness by antagonizing β-catenin via the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes acted as transcriptional platforms that integrated and funneled both tumor-suppressive and oncogenic signals into the expression of genes that control colon cancer stemness.

Co-targeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers.

Both in vitro and in vivo experiments demonstrate that treating myeloma cells with PD-L1 antibodies post-chemotherapy significantly enhances the killing efficiency of activated T cells, compared to sequential treatment with chemotherapy and PD-L1 antibodies. This research not only uncovers a pivotal regulatory mechanism of PD-L1 upregulation but also provides a compelling rationale for the integration of chemotherapy and immunotherapy in myeloma treatment.

PAF1 depletion was also associated with decreased pluripotent TFs and other CSC markers. This study provides a novel regulatory mechanism of docetaxel resistance in PCa through PAF1 and establishes clinically relevant docetaxel-resistant PCa cell lines.

Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.

Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.