title: Tumor suppressor long non-coding RNA, MT1DP is negatively regulated by YAP and Runx2 to inhibit FoxA1 in liver cancer cells.
abstract: Recent studies are indicative for strong carcinogenetic roles of Runt related transcription factor 2 (Runx2) and Yes associated protein (YAP) in several cancer types. However, whether and how the interaction between Runx2 and YAP plays a role in liver tumorigenesis still remain illusive. Here, we identified a close relationship between Runx2 and YAP in liver cancer cells. Runx2 had a positive role on YAP expression and vice versa. We also found that Rux2 and YAP were capable of inhibiting long non-coding RNA (lncRNA), Metallothionein 1D, Pseudogene (MT1DP) expression through direct promoter binding. Overexpression of MT1DP resulted in reduced cell proliferation and colony formation in soft agar, but increased apoptosis in liver cancer cells, whereas knockdown of this lncRNA had the opposite effect, indicating that MT1DP acts as a tumor suppressor. Furthermore, MT1DP was revealed as a negative regulator of Alfa-fetoprotein (AFP), a classic liver cancer tumor marker, through inhibiting protein synthesis of Forkhead box A1 (FoxA1), an important transcription factor in liver development and cancer progression. Furthermore, we found that FoxA1 plays a positive role on YAP and Runx2 expression. Specially, opening the compacted chromatin by FoxA1 around CREB binding site within the YAP promoter facilitates CREB-mediated YAP transcription. Finally, MT1DP-inhibited in vivo liver cancer cell growth could be rescued by a combination of overexpression of FoxA1, Runx2 and YAP. Taken together, the close relationship between Rnux2 and YAP plays a pro-carcinogenetic role in liver cancer cells through inhibiting tumor suppressor lncRNA, MT1DP in a FoxA1 dependent manner.
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yu
authors.affiliation: School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Weng
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai 200071, China.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: sunfenyong@126.com.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: karajan2@163.com.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000509:alpha-Fetoproteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050659:Core Binding Factor Alpha 1 Subunit; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D010750:Phosphoproteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000509:alpha-Fetoproteins
keywords: Alfa-fetoprotein; CREB; Long non-coding RNA; Promoter; Tumorigenesis