Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma
Authors: Jingxuan Pan
Jing Zhang
Shenglan Liu
Qianyun Ye
Journal: Molecular cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Apoptosis; Cancer stem-like cells; Cell motility; KLF4; Liver metastasis
Affiliations: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, People's Republic of China., State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, People's Republic of China. .

Abstract:  Background: Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. Methods: The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. Results: The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. Conclusions: In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM. 

Retracted: No

PubPeer comments:
 Figure 4D. * Red boxes: In the 92.1 column, the Nanog and Sox2 panels appear to look similar. ![file] , 
 Dear Madam Sir, Thanks for your kind message. I will inquire the person who was conducting the relevant experiments, and take a thorough investigation. If there is an error, we will definitely take steps to make correction. I am visiting abroard. It will take me 2 weeks to return China. Thanks. Jingxuan Pan , 
 The authors should also check the problem of Fig. 2C. ![file] , 
 Also Fig. 1B, similar bands with different exposure. ![file] , 
 Much more similar than you could expect again. ![file] , 
 #1 Hi, Dr. Elisabeth M Bik, I am the first author Jing Zhang. I carefully checked the original data and admit the error in immunoblot in Figure 4D as you pointed out. The specific immunoblot band was accidentally and incorrectly re-utilized for both Nanog and Sox2 for 92.1 cells. This error took place during preparation of figures with photoshop microsoftware. The high-resolution scans of the original immunoblots were appended. I deeply apologize for the mistakes to readers and appreciate your pointing out. However, I would like to mention that these errors do not affect the conclusions of the study. The authors have requested the Journal to give an erratum. Thanks. Jing Zhang Sox2 original data for 92.1 and Mel270 cells in Figure 4D ![file] Nanog original data for 92.1 and Mel270 cells ![file] #3 Hi, Dr. Platycheirus Stegnus, I carefully checked the original data and admit the error in immunoblot in Figure 2C as you pointed out. The specific immunoblot band was accidentally duplicated for Actin in both 92.1 and Mel270 cells. This error took place during preparation of figures with photoshop microsoftware. The high-resolution scans of the original immunoblots were appended. I deeply apologize for the mistake to readers and appreciate your pointing out. However, I would like to mention that these errors do not affect the conclusions of the study. The authors have requested the Journal to give an erratum. Thanks. Jing Zhang Actin original data for 92.1 and Mel270 cells in Figure 2C ![file] #4 Hi, Dr. Platycheirus Stegnus, I carefully checked the original data in Figure 1B as you pointed out. The specific immunoblot bands for p-RNA Pol II (S2) and p-RNA Pol II (S7) in Omm2.3 cells were correct. The high-resolution scans of the original immunoblots were appended. Thanks. Jing Zhang p-RNA Pol II (S2) and p-RNA Pol II (S7) original data for Omm2.3 cells in Figure 1B ![file] #5 Hi, Dr. Platycheirus Stegnus, I carefully checked the original data and admit the error in immunoblot in Figure 1C as you pointed out. The specific immunoblot band was accidentally duplicated for p-YAP (S127) in both Mel270 and Omm2.3 cells. This error took place during preparation of figures with photoshop microsoftware. The high-resolution scans of the original immunoblots were appended. I deeply apologize for the mistakes to readers and appreciate your pointing out. However, I would like to mention that this error do not affect the conclusions of the study. The authors have requested the Journal to give an erratum. Thanks. Jing Zhang p-YAP (S127) original data for Mel270 and Omm2.3 cells in Figure 1C ![file] , 
 Correction, October 2021: https: molecular-cancer.biomedcentral.com articles 10.1186 s12943-021-01410-x  Following publication of the original article [1], minor errors were identified in the images presented in Figs. 1, 2 and 4; specifically: - Fig. 1b: immunoblot band for p-RNA Pol II (S2), Omm2.3 cells, has been replaced with the correct image - Fig. 1c: immunoblot bands for p-YAP (S127), in both Mel270 and Omm2.3 cells, have been replaced with the correct images - Fig. 2c: immunoblot band for Actin, Mel270 cells, has been replaced with the correct image - Fig. 4d: immunoblot bands for Sox2, in both 92.1 and Mel270 cells, have been replaced with the correct images The corrected figures are given below. The correction does not have any effect on the results or conclusions of the paper. The original article has been corrected. ,