UBE2S targets RPL26 for ubiquitination and degradation to promote non-small cell lung cancer progression via regulating c-Myc.

Multiple studies have shown that E2 conjugating enzyme family are dysregulated in various cancers and associated with tumor progression and poor prognosis. In present study, we screened and confirmed that UBE2S is one of the E2 conjugating enzymes highly expressed in non-small cell lung cancer (NSCLC), and it plays an oncogenic role by enhancing cell proliferation, migration and stemness in vitro. Using immunoprecipitation technology combined with mass spectrometry assay, we identified ribosomal protein RPL26 as the substrate protein of UBE2S in NSCLC. At the molecular level, overexpression of UBE2S accelerated the ubiquitination and degradation of RPL26, thus upregulating c-Myc to enhance the progression of NSCLC. In addition, the results of a xenograft experiment showed that inhibiting UBE2S could suppress RPL26-c-Myc mediated NSCLC tumor growth in vivo. Our data provided mechanistic evidence supporting the existence of a novel UBE2S-RPL26-c-Myc axis and its critical contribution to progression of NSCLC.

NR2C2 of macrophages promotes inflammation via NF-κB in LPS-induced orchitis in mice.

In brief: Bacterial infection can induce testicular inflammation and damage male fertility. This paper reveals the role of nuclear receptor subfamily 2 group C member 2 (NR2C2) in macrophage cells in orchitis caused by bacterial endotoxin lipopolysaccharide (LPS) infection. Abstract: Bacterial infection and induced inflammation are important causes of male infertility. Here, we described the characteristics of expression and the regulatory role of NR2C2 in testicular inflammatory injury induced by infection with the bacterial endotoxin LPS. We found that NR2C2 was highly expressed in the testes and the expression of NR2C2 was upregulated in testicular macrophages in the LPS-induced mouse orchitis model in vivo. In primary testicular macrophages and RAW264.7 cells in vitro, RNA interference with the Nr2c2 gene downregulated the expression of inflammatory factors such as IL-1ß and IL-6. In addition, the knockdown of NR2C2 in macrophages alleviated the inhibitory effect of the inflammatory supernatant secreted by the macrophages on the proliferation of spermatogonia GC-1 SPG cells. Mechanistically, NR2C2 activated NF-κB signaling by binding with DR elements in the promotor of the Nfκb gene and promoted the development of inflammation. These data are the first to confirm that during LPS-induced bacterial infection, NR2C2 plays a proinflammatory role by activating IL-1ß and IL-6 via the NF-κB pathway in macrophages, consequently inhibiting the proliferation of spermatogonia and damaging the quality of sperm. Our findings reveal the important role of NR2C2 in testicular inflammatory injury induced via LPS and provide a new potential target and a molecular basis for the treatment of male infertility caused by bacterial infection.

Chromodomain helicase DNA-binding domain 2 maintains spermatogonial self-renewal by promoting chromatin accessibility and mRNA stability.

Chromodomain helicase DNA-binding domain 2 (CHD2) is a chromatin remodeling factor involved in many developmental processes. However, its role in male germ cell development has not been elucidated. Here, we confirm that CHD2 expression is enriched in the male germline. In a heterozygous knockout mouse model of Chd2 (Chd2 +/-), we demonstrated that Chd2 haploinsufficiency resulted in testicular developmental delay, an increased rate of abnormal sperm, and impaired fertility in mice. In vitro experiments in mouse spermatogonia showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanistically, CHD2 maintains the enrichment of H3K4me3 in the Ccnb1 and Ccnd2 promotors, consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, CHD2 interacts with the cleavage stimulation factor CSTF3 and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first study to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal.