Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediatedMAPK signaling

Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

Fsh-Pc-Sce complex mediates active transcription of Cubitus interruptus （Ci）

表明小径的刺猬(Hh ) 在胚胎的开发和成年织物动态平衡起重要作用。如此的生物功能被抄写因素肘脉 interruptus (Ci ) 调停。然而，受动器 Ci 本身的 transcriptional 规定糟糕被调查。通过一幅基于 RNAi 的基因屏幕，我们识别了那女性无菌(1 ) homeotic (Fsh ) ，抄写激活剂，直接激活 Ci 抄写。生物化学试金在 Fsh 之中表明了物理相互作用，性梳子额外(Sce ) ，并且 Polycomb (Pc ) 。功能的试金进一步证明 Pc 和 Sce 为 Ci 被要求表示，没被 Engrailed 的 derepression 多半调停，) ， Ci 的一个抑压者，在 Pc 或 Sce 异种房间。最后，我们提供证明 Pc/Sce 在 Ci 地点便于 Fsh 的绑定并且在 Fsh 和 Pc 之间的物理相互作用为调停 Fsh 的 Ci 抄写是必要的证据。一起拿，我们不仅揭开那 Ci 被复杂的 Fsh-Pc-Sce transcriptionally 调整而且在 transcriptional 为在 Fsh 和 PcG 蛋白质之间的协作提供证据规定。

Hedgehog in the Drosophila testis niche:what does it do there?

Stem cell niche is a specialized microenvironment crucial to self-renewal.The testis in Drosophila contains two dif-ferent types of stem cells,the germline stem cells and the somatic cyst stem cells that are sustained by their respec-tive niche signals,thus is a good system for studying the interaction between the stem cells and their hosting niche.The JAK-STAT and BMP pathways are known to play critical roles in the self-renewal of different kinds of stem cells,but the roles of several other pathways have emerged recently in a complex signaling network in the testis niche.Reports of independent observations from three research groups have uncovered an important role of Hedgehog(Hh)in the Drosophila testis niche.In this review,we summarize these recent fi ndings and discuss the interplay between the Hh signaling mechanisms and those of the JAK-STAT and BMP pathways.We also dis-cuss directions for further investigation.