Project description:ARID1A functions as a vital tumor suppressor whose activity usually depends on the SWI/SNF chromatin remodeling complex. ARID1A is highly mutated across human cancers, and its deficiency has been found to promote immunogenicity through impaired mismatch repair and elevated tumor mutation burden. However, little is known about the SWI/SNF-independent function of ARID1A and the subsequent consequences. Here, we report a novel mechanism of action that ARID1A maintains heterochromatin integrity and silences endogenous satellite/retroelements, independent of SWI/SNF and microsatellite instability. Mechanistically, ARID1A recruits TRIM28 to keep the rigidity of heterochromatin. Loss of ARID1A displaces SETDB1 from TRIM28-contraining heterochromatin complex to induce the derepression of H3K9me3 at endogenous satellite/retroelement regions. The unleashed satellites and retroelements resulting from impaired ARID1A-TRIM28 interaction trigger type-I interferon immune responses, promoting tumor progression and sensitivity to PD1 blockade through both RNA- and DNA-sensing pathways. Our results shed light on the SWI/SNF-independent function of ARID1A to necessarily maintain heterochromatin integrity and safeguard the immunogenicity, potentiating the disruption of ARID1A-TRIM28 interaction as a strategy to convert ARID1A-wildtype tumors into hot to strengthen the therapeutic efficacies.

2025-11-24 | GSE239728 | GEO

ARID1A recruits TRIM28 for the essential remodeling of heterochromatin independent of SWI/SNF [RNA-seq]

2025-11-24 | GSE239727 | GEO

Secretome analysis of human A549 Lung cancer cells harboring LKB1 mutations.

Project description:STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation. Elucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) tumor suppressor appears to be inactivated in human cancer, however, somatic missense mutations also occur. Despite of our increased knowledge about LKB1 function, the role/s of these alterations in cancer are mostly unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three, out of the four mutants, lost their tumor suppressor capabilities and showed a deficient kinase activity. The remaining mutant conserved the enzymatic activity, but conferred an increased cell motility. Mechanistically, LKB1 mutants promoted the differential gene expression regulation of vesicle trafficking regulating molecules, adhesion molecules and cytokines, that correlated with the identified protein networks associated to the comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one of them induced inflammation and hemorrhagic tumors that correlated with the deregulated levels of cytokines. Altogether, our findings uncover oncogenic roles of LKB1 somatic mutations helping to understand their contribution to cancer.

2021-09-09 | PXD018041 | Pride

p53 directly represses human LINE1 transposons

Project description:p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germ line tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5’UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

2020-12-01 | GSE159134 | GEO

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells

2014-05-29 | E-GEOD-57989 | biostudies-arrayexpress

Mus musculus

Project description:TRIM28 silences endogenous retroviruses in neural progenitor cells

| PRJNA196678 | ENA

Project description:Single chromosome aneuploidy commonly functions as a tumor suppressor

| PRJNA356424 | ENA