P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression

作者全名:"Li, Quanfu; Liu, Yiyang; Wu, Jingxian; Zhu, Zewen; Fan, Jianjun; Zhai, Linhui; Wang, Ziruoyu; Du, Guiping; Zhang, Ling; Hu, Junchi; Ma, Dengke K.; Liu, Jun O.; Huang, Hai; Tan, Minjia; Dang, Yongjun; Jiang, Wei"

作者地址:"[Li, Quanfu; Liu, Yiyang; Zhu, Zewen; Wang, Ziruoyu; Jiang, Wei] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China; [Wu, Jingxian] First Affiliated Hosp Chongqing Med Univ, Chongqing Med Univ, Coll Basic Med, Mol Med Diagnost & Testing Ctr,Dept Pathol,Affilia, Chongqing 400016, Peoples R China; [Fan, Jianjun; Hu, Junchi; Dang, Yongjun] Chongqing Med Univ, Coll Pharm, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400016, Peoples R China; [Zhai, Linhui] Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai 200434, Peoples R China; [Du, Guiping] Zhejiang Univ, Womens Hosp, Sch Med, Hangzhou 310058, Peoples R China; [Zhang, Ling] Chongqing Med Univ, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Affiliated Hosp 2, Chongqing 400016, Peoples R China; [Ma, Dengke K.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Physiol, San Francisco, CA 94158 USA; [Liu, Jun O.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21287 USA; [Huang, Hai] Zhejiang Univ, Dept Cell Biol, Sch Med, Hangzhou 310058, Peoples R China; [Huang, Hai] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou 310058, Peoples R China; [Tan, Minjia] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China"

通信作者:"Jiang, W (通讯作者),Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China.; Dang, YJ (通讯作者),Chongqing Med Univ, Coll Pharm, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400016, Peoples R China."

来源:LEUKEMIA

ESI学科分类:CLINICAL MEDICINE

WOS号:WOS:001251877800001

JCR分区:Q1

影响因子:11.4

年份:2024

卷号:38

期号:8

开始页:1751

结束页:1763

文献类型:Article

关键词: 

摘要:"Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma."

基金机构:National Natural Science Foundation of China (National Science Foundation of China)

基金资助正文:"We thank support from prof. Yun Zhao from Chinese Academy of Sciences, prof. Hai Jiang from Chinese Academy of Sciences, prof. Yanhui Xu and Huirong Yang from Fudan University."