CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH..
Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) - 11(2024), 14 vom: 24. Apr., Seite e2306827 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Kai [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 11.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/advs.202306827 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367975629 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367975629 | ||
| 003 | DE-627 | ||
| 005 | 20240425232815.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240203s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/advs.202306827 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM367975629 | ||
| 035 | |a (NLM)38308184 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Kai |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.04.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH. | ||
| 520 | |a Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a HFD | |
| 650 | 4 | |a YAP1 | |
| 650 | 4 | |a cholesterol metabolism | |
| 650 | 4 | |a hepatocellular carcinoma(HCC) | |
| 650 | 7 | |a Cholesterol |2 NLM | |
| 650 | 7 | |a 97C5T2UQ7J |2 NLM | |
| 650 | 7 | |a HMGCS1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.3.3.10 |2 NLM | |
| 650 | 7 | |a Hydroxymethylglutaryl-CoA Synthase |2 NLM | |
| 650 | 7 | |a EC 2.3.3.10 |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a SPOP protein, human |2 NLM | |
| 650 | 7 | |a Ubiquitin |2 NLM | |
| 650 | 7 | |a YAP1 protein, human |2 NLM | |
| 650 | 7 | |a YAP-Signaling Proteins |2 NLM | |
| 700 | 1 | |a Zhang, Jiayu |e verfasserin |4 aut | |
| 700 | 1 | |a Lyu, Haiwen |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jinneng |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Wenxia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Haidan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yijing |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Hairong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Mengan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Caiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Kang |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Lishi |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Weijie |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guolin |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Yunle |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Runxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Xinhui |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Baifu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Zhongguo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Haipeng |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Mong-Hong |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Advanced science (Weinheim, Baden-Wurttemberg, Germany) |d 2014 |g 11(2024), 14 vom: 24. Apr., Seite e2306827 |w (DE-627)NLM252851455 |x 2198-3844 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2024 |g number:14 |g day:24 |g month:04 |g pages:e2306827 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/advs.202306827 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2024 |e 14 |b 24 |c 04 |h e2306827 | ||