MAZ Coordinates With HDAC1 to Promote Hepatocarcinoma Proliferation and Metastasis Through Transcriptional Repression of CSK.

The transcription factor Myc-associated zinc finger protein (MAZ) is highly expressed in various malignant tumors, and it is known to activate the expression of a large number of proto-oncogenes through transcription. However, the specific molecular mechanism of how MAZ regulates transcriptional repression in hepatocarcinoma remains unclear. To identify the interacting proteins of MAZ, we employed immunoaffinity purification followed by silver-stain mass spectrometry. RNA-seq analysis, RT-PCR, and ChIP assays were utilized to examine the target genes and signaling pathways coregulated by MAZ and HDAC1. Additionally, we conducted EdU incorporation, colony formation, growth curve, TUNEL, transwell, and wound-healing assays, along with immunohistochemical staining, in vivo tumor xenografts, and bioluminescence metastasis assays, to explore the role of the MAZ/HDAC1 complex in tumorigenesis. Our findings revealed that MAZ binds to the transcriptional inhibitory complexes HDAC1, RBBP7, and CUL4B. Transcriptome analysis revealed that MAZ and HDAC1 cooperatively regulate the expression of the CSK gene. Knockdown of either MAZ or HDAC1 activates CSK expression, subsequently inhibiting the MAPK/ERK, STAT3, and PI3K/AKT signaling pathways, thereby suppressing the proliferation and metastasis of hepatocellular carcinoma cells. The proliferation and metastasis phenotypes induced by MAZ knockdown can be rescued by simultaneous knockdown of CSK. In vivo experiments have demonstrated that MAZ knockdown inhibits tumorigenesis and metastasis in mice. Our findings highlight a novel mechanism wherein MAZ plays a transcriptional inhibitory role by recruiting HDAC1 to catalyze histone deacetylation, and the MAZ/HDAC1 complex inhibits CSK expression, thus promoting tumor proliferation and metastasis.