Setd2 deficiency promotes gastric tumorigenesis through inhibiting the SIRT1/FOXO pathway.

Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.

SETD2 deficiency promotes renal fibrosis through the TGF-ß/Smad signalling pathway in the absence of VHL.

BACKGROUND: Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. METHODS: Kidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel-Lindau (VHL) double-knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis. RESULTS: SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor-ß (TGF-ß)/Smad signalling pathway, thereby preventing the activation of the TGF-ß/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF-ß/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL. CONCLUSIONS: Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-ß/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips.

The identification of prostate stem/progenitor cells and characterization of the prostate epithelial cell lineage hierarchy are critical for understanding prostate cancer initiation. Here, we characterized 35,129 cells from mouse prostates, and identified a unique luminal cell type (termed type C luminal cell (Luminal-C)) marked by Tacstd2, Ck4 and Psca expression. Luminal-C cells located at the distal prostate invagination tips (termed Dist-Luminal-C) exhibited greater capacity for organoid formation in vitro and prostate epithelial duct regeneration in vivo. Lineage tracing of Luminal-C cells indicated that Dist-Luminal-C cells reconstituted distal prostate luminal lineages through self-renewal and differentiation. Deletion of Pten in Dist-Luminal-C cells resulted in prostatic intraepithelial neoplasia. We further characterized 11,374 human prostate cells and confirmed the existence of h-Luminal-C cells. Our study provides insights into the prostate lineage hierarchy, identifies Dist-Luminal-C cells as the luminal progenitor cell population in invagination tips and suggests one of the potential cellular origins of prostate cancer.

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming.

Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells' normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.

Organoid technology in cancer precision medicine.

Organoid technology has been remarkably improved over the last decade. Various organoids have been derived from different types of tissues and recapitulate their organ-specific gene expression signatures, particular tissue spatial structures and functions of their original tissue. The patient-derived organoids (PDOs) have been used to elucidate crucial scientific questions, including the relationships between genetic/epigenetic alterations and drug responses, cell plasticity during disease progressions, and mechanisms of drug resistances. With the great expectations, PDOs will be widely used to facilitate the personalized medical decisions, which have the potential to profoundly improve patient outcomes. In this review, we will discuss the developmental details, current achievements, applications and challenges of organoid technology in precision cancer medicine.