SIN3A and SIN3B differentially regulate breast cancer metastasis

Abstract

SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.

A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression

“…The low expression of SIN3A mRNA also decreases survival rates in non-small cell lung cancer and renal cell carcinomas 33 . In a previous report, SIN3A -knock down cells showed a significant increase in invasive activity, leading to an increased rate of metastasis 34 . Metastasis to other organs may be involved in the breast cancer relapse.…”

Differential complex formation via paralogs in the human Sin3 protein interaction network

“…In addition to having critical roles during mammalian development, SIN3A and SIN3B also have contrasting influences on breast cancer cell metastasis. SIN3A was identified as a suppressor of metastasis, whereas SIN3B was proposed to be pro-metastatic (9). However, the mechanisms responsible for divergent influences on development as well as cancer cell metastatic potential remain poorly understood.…”

Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3 HDAC complex

“…Functions ascribed to Rpd3/Sin3 complexes are varied and appear to be context dependent. Although typically referred to as corepressor complexes due to the presence of a histone deacetylase subunit, Rpd3/Sin3 complexes have been associated with both activation and repression of gene expression (Cantor and David, 2017;Cheng et al, 2014;Halder et al, 2017;Lewis et al, 2016;Liu and Pile, 2016;Saha et al, 2016;Saunders et al, 2017;van Oevelen et al, 2008van Oevelen et al, , 2010. In addition, the yeast Rpd3/Sin3S complex has been shown to repress cryptic transcription initiation in transcribed regions and to suppress antisense transcription initiation at promoters (Carrozza et al 2005;Churchman and Weissman 2011).…”