Switch-Independent 3A: An Epigenetic Regulator in Cancer with New Implications for Pulmonary Arterial Hypertension

Abstract

Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA, play a crucial role in the regulation of gene expression and are pivotal in biological processes like apoptosis, cell proliferation, and differentiation. SIN3a serves as a scaffold protein and facilitates interactions with transcriptional epigenetic partners and specific DNA-binding transcription factors to modulate gene expression by adding or removing epigenetic marks. However, the activation or repression of gene expression depends on the factors that interact with SIN3a, as it can recruit both transcriptional activators and repressors. The role of SIN3a has been extensively investigated in the context of cancer, including melanoma, lung, and breast cancer. Our group is interested in defining the roles of SIN3a and its partners in pulmonary vascular disease. Pulmonary arterial hypertension (PAH) is a multifactorial disease often described as a cancer-like disease and characterized by disrupted cellular metabolism, sustained vascular cell proliferation, and resistance to apoptosis. Molecularly, PAH shares many common signaling pathways with cancer cells, offering the opportunity to further consider therapeutic strategies used for cancer. As a result, many signaling pathways observed in cancer were studied in PAH and have encouraged new research studying SIN3a’s role in PAH due to its impact on cancer growth. This comparison offers new therapeutic options. In this review, we delineate the SIN3a-associated epigenetic mechanisms in cancer and PAH cells and highlight their impact on cell survival and proliferation. Furthermore, we explore in detail the role of SIN3a in cancer to provide new insights into its emerging role in PAH pathogenesis.

Hypertension as predictive factor for bevacizumab-containing first-line therapy in metastatic breast and colorectal cancer in BRECOL (GEICAM/2011-04) study

“…Of the 850,000 methylation sites analyzed, distributed throughout the genome, 27 were identified (18 of them corresponding to the genes FMNL2, METTL3, ACOT6, SCARNA20, PREX1, DNAI2, RAET1G, KCNJ8, GDF7, SYNPO2, CUGBP1, FRMD8, MKL2, HIF1A, TMEM177, UTP23, PXK and TNPO1) that were associated with the development of early tumor shrinkage secondary to BVZ. Among the genes identified are some linked to BP regulation and angiogenesis and AHT such as HIF1A or METTL3 [ 20 , 21 ]. Future studies should clarify the predictive role to antiangiogenic treatments of this methylation profile of 27 genes related to AHT secondary to BVZ-containing treatment.…”

Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex

“…The integrity of the Sin/HDAC complex is crucial for central nervous system development (1), methionine catabolism, and glycolysis/gluconeogenesis (3). It also plays a significant role in breast cancer metastasis (4), activating autophagy (5), contributing to pulmonary arterial hypertension (6), and influencing triple-negative breast cancer (7). In addition to the SIN3A/B paralogues, several proteins bind with the Sin/HDAC complexes including RBBP4/RBBP7 and HDAC1/2, which are shared with other transcriptional repressor complexes, and the Sin3-associated proteins SAP30/SAP30L, SUDS3, BRMS1/BRMS1L, ING1/2, ARID4A/B, SAP18, FAM60A, and SAP25 (8)(9)(10)(11).…”