SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

Abstract

Deletions of chromosome 1p36 are common in cancers; however, despite extensive studies, there has been limited success for discovering candidate tumor suppressors in this region. SRARP has recently been identified as a novel corepressor of the androgen receptor (AR) and is located on chromosome 1p36. Here, bioinformatics analysis of large tumor datasets was performed to study SRARP and its gene pair, HSPB7. In addition, using cancer cell lines, mechanisms of SRARP and HSPB7 regulation and their molecular functions were investigated. This study demonstrated that SRARP and HSPB7 are a gene pair located 5.2 kb apart on 1p36.13 and are inactivated by deletions and epigenetic silencing in malignancies. Importantly, SRARP and HSPB7 have tumor suppressor functions in clonogenicity and cell viability associated with the downregulation of Akt and ERK. SRARP expression is inversely correlated with genes that promote cell proliferation and signal transduction, which supports its functions as a tumor suppressor. In addition, AR exerts dual regulatory effects on SRARP, and although an increased AR activity suppresses SRARP transcription, a minimum level of AR activity is required to maintain baseline SRARP expression in AR+ cancer cells. Furthermore, as observed with SRARP, HSPB7 interacts with the 14‐3‐3 protein, presenting a shared molecular feature between SRARP and HSPB7. Of note, genome‐ and epigenome‐wide associations of SRARP and HSPB7 with survival strongly support their tumor suppressor functions. In particular, DNA hypermethylation, lower expression, somatic mutations, and lower copy numbers of SRARP are associated with worse cancer outcome. Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis. In summary, SRARP and HSPB7 are tumor suppressors that are commonly inactivated in malignancies. SRARP inactivation is an early event in carcinogenesis that is strongly associated with worse survival, presenting potential translational applications.

Steroid receptor‐associated and regulated protein is a biomarker in predicting the clinical outcome and treatment response in malignancies

“…1 In addition, these effects are associated with the downregulation of Akt and extracellular signal-regulated kinases (ERK) signaling, and SRARP expression inversely correlates with genes that promote cell proliferation and signal transduction, further supporting its functions as a tumor suppressor. 1 It is also notable that 1p36 is frequently deleted in malignancies and 1p36.1 losses occur in 34% of tumors. 3 However, despite extensive studies, there has been limited success for identifying candidate tumor suppressors on chromosome 1p36.…”

“…2 In this process, AR exerts dual regulatory effects on SRARP and although an increased AR activity suppresses SRARP transcription, a minimum level of AR activity is required to maintain baseline SRARP expression in AR+ cancer cells. 1,2 SRARP, in turn, interacts with AR as a corepressor and negatively regulates the AR-mediated induction of prolactin-induced protein and AR reporter activity. 2 SRARP also has a relatively higher expression in breast tumors that are estrogen receptor positive (ER+), lower grade, and lobular histology.…”

“…6 Therefore, while SRARP is broadly inactivated in malignancies and function as a tumor suppressor, when expressed in AR+ cells, this gene carries a transcriptional regulatory function as a corepressor of AR. 1,2 Importantly, genome and epigenome-wide associations of SRARP with survival strongly support its function as a tumor suppressor. 1 In this respect, DNA hypermethylation, lower expression, somatic mutations, and lower copy-number of SRARP are strongly associated with worse cancer outcome.…”

“…1,2 Importantly, genome and epigenome-wide associations of SRARP with survival strongly support its function as a tumor suppressor. 1 In this respect, DNA hypermethylation, lower expression, somatic mutations, and lower copy-number of SRARP are strongly associated with worse cancer outcome. 1 Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis.…”

“…1 In this respect, DNA hypermethylation, lower expression, somatic mutations, and lower copy-number of SRARP are strongly associated with worse cancer outcome. 1 Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis. 1 Therefore, genomic and epigenomic inactivation of SRARP may provide valuable prognostic markers in malignancies and normal adjacent tissues with translational applications, and additional studies are required to explore the potential applications of SRARP as a biomarker.…”