ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM

Abstract

The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated down-regulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, down-regulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens. Implications Together these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications.

Upregulation of ZBTB7A exhibits a tumor suppressive role in gastric cancer cells

“…Frequent deletions in the ZBTB7A gene locus have been reported in a number of different types of cancer (18)(19)(20). In the present study, it was hypothesized that ZBTB7A may function as a tumor suppressor in GC.…”

“…Frequent loss of ZBTB7A and its association with patient overall survival in the human gastric adenocarcinoma database. As frequent chromosomal deletions at the ZBTB7A gene locus have been reported in a number of different types of human cancer (18)(19)(20), in the present study the ZBTB7A gene was investigated in human gastric adenocarcinoma. CNA, mRNA expression and overall survival data from 441 patients were downloaded from the TCGA provisional dataset.…”

“…TCGA provides a large amount of data, serving an important resource for the field of cancer research (31). Previously, a number of studies have demonstrated that the ZBTB7A gene locus exhibited frequent chromosomal deletions in a number of different types of human cancer (18)(19)(20). In the present study, data mining of ZBTB7A in TCGA gastric adenocarcinoma dataset was performed.…”

“…Previously, ZBTB7A has also been reported to be novel proto-oncogene in different types of cancer, including breast cancer, NSCL, lymphoma and ovarian cancer (13)(14)(15)(16)(17). However, the frequent chromosomal deletion of the ZBTB7A gene locus in numerous types of human cancer (18)(19)(20) contradicts its proto-oncogenic role. Previous studies indicate that ZBTB7A works as a tumor suppressor in melanoma (20), PTEN-loss background prostate cancer (21) and colonic cancer (22).…”

“…However, the frequent chromosomal deletion of the ZBTB7A gene locus (19p13.3) in multiple types of human cancer (18)(19)(20) suggests it is not a proto-oncogene. This evidence implies that the function of ZBTB7A is determined by its context in solid tumors.…”