Molibresib

The bromodomain and extraterminal domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor because of an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, bromodomain-containing protein 4 (BRD4) binds to estrogen receptor binding sites and activates transcription of critical oncogenes such as MYC, independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator reduces BRD4's enhancer occupancy. Profiling changes of the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6 and the polymerase-associated factor 1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.

The ribosomal protein L22-like1 (RPL22L1) is a constituent of the 60 S ribosomal subunit whose function in lung adenocarcinoma (LUAD) remains ambiguous. This study aims to elucidate the role of RPL22L1 in LUAD through a thorough analysis and experimental validation. Our findings indicate that RPL22L1 exhibits abnormal expression patterns in various cancer types, including LUAD. Moreover, a statistically significant association was observed between elevated levels of RPL22L1 expression in LUAD patients and several clinical parameters, such as pathological stage (p = 0.0083) and gender (p = 0.0038). The high expression of RPL22L1 in LUAD demonstrated a significant association with poorer overall survival (OS) (p = 0.005), progression-free survival (PFS) (p = 0.027), and disease-specific survival (p = 0.015). The expression of RPL22L1 in LUAD (p = 0.005) was identified as an independent prognostic factor. Additionally, RPL22L1 expression in LUAD was found to be correlated with immune infiltration, immune checkpoint genes, TMB/MSI, and mRNAsi. Notably, the expression of RPL22L1 exhibited significant negative correlations with 1-BET-762, Trametinib, and WZ3105 in LUAD. The RPL22L1 gene exhibited up-regulation in multiple individual cells of LUAD, leading to a comparatively shorter PFS in the RPL22L1 variant group as opposed to the RPL22L1 variant-free group in LUAD. Significantly increased expression of RPL22L1 was noted in LUAD cell lines, where it was found to enhance the growth and metastasis of LUAD cells by suppressing the MDM2/P53 signaling pathway. Therefore, RPL22L1 may serve as a promising prognostic biomarker and therapeutic target for patients with LUAD.