PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression

Zheng, Yi; Meng, Xue; Shen, Hong; Li, Xiao Guang; Ma, Ding; Gong, Yue; Liu, Yi-Rong; Qiao, Feng; Xie, Haiyang; Bi, Lijun; Sun, Wei; Zhao, Hai Yun; Yao, Ling; Zuo, Wenbao; Li, Da Qiang; Wang, Peng; Hu, Xin; Shao, Zhimin

doi:10.1158/0008-5472.can-17-3514

Cited by 69 publications

(79 citation statements)

References 47 publications

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“…To further validate the correlation of gene expression and MeGDP or MBS, we performed GPS in two breast cell lines, MCF-10A and MCF-10A-1H (Zheng et al 2018). We found the correlation between gene expression and MeGDP or MBS were consistent with the previous results (Supplemental Fig.…”

Section: Methylation Boundary Shift In the Promoter Region Modulates supporting

confidence: 87%

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks

Jin

et al. 2019

Genome Res.

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Aberrant DNA methylation is a distinguishing feature of cancer. Yet, how methylation affects immune surveillance and tumor metastasis remains ambiguous. We introduce a novel method, Guide Positioning Sequencing (GPS), for precisely detecting whole-genome DNA methylation with cytosine coverage as high as 96% and unbiased coverage of GC-rich and repetitive regions. Systematic comparisons of GPS with whole-genome bisulfite sequencing (WGBS) found that methylation difference between gene body and promoter is an effective predictor of gene expression with a correlation coefficient of 0.67 (GPS) versus 0.33 (WGBS). Moreover, Methylation Boundary Shift (MBS) in promoters or enhancers is capable of modulating expression of genes associated with immunity and tumor metabolism. Furthermore, aberrant DNA methylation results in tissue-specific enhancer switching, which is responsible for altering cell identity during liver cancer development. Altogether, we demonstrate that GPS is a powerful tool with improved accuracy and efficiency over WGBS in simultaneously detecting genome-wide DNA methylation and genomic variation. Using GPS, we show that aberrant DNA methylation is associated with altering cell identity and immune surveillance networks, which may contribute to tumorigenesis and metastasis.

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Section: Methylation Boundary Shift In the Promoter Region Modulates supporting

confidence: 87%

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks

Jin

et al. 2019

Genome Res.

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“…PHF5A is a highly conserved PHD-zinc finger domain protein that facilitates interactions between the U2 snRNP complex and DNA/RNA helicases [25]. Additionally, PHF5A facilitates interactions with specific histone marks on chromatin-bound nucleosomes through its PHD domain [26][27][28][29]. PHF5A inhibition also compromised GSC tumor formation in vivo and inhibited the growth of established GBM patient-derived xenograft tumors [30].…”

Section: Discussionmentioning

confidence: 99%

CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A

Liu

et al. 2020

BMC Cancer

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Background: Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; however, its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action. Methods: By using immunohistochemistry, the expression levels were evaluated in both cancer and non-cancerous tissues. Subsequently, CHD4 knockdown and overexpression strategies were employed to investigate the effects of CHD4 on cell proliferation, migration, along with the growth and formation of tumors in a xenografts mouse model. The protein expression levels of CHD4, PHF5A and ROCK/RhoA markers were determined by Western blot analysis. Results: Compared with non-cancerous tissues, CHD4 was overexpressed in cancer tissues and CHD4 expression levels were closely related to clinical parameters of NSCLC patients. In H292 and PC-9 cell lines, CHD4 overexpression could promote the proliferative and migratory potential of NSCLC cells. Furthermore, downregulation of CHD4 could reduce the proliferative and migratory ability in A549 and H1299 cell lines. Meanwhile, knockdown of CHD4 could decrease the tumorigenicity in nude mice. Finally, we demonstrated that one of the mechanisms underlying the promotive effect of CHD4 on NSCLC proliferation and migration may be through its interaction with PHD finger protein 5A (PHF5A) and subsequent activation of the RhoA/ROCK signaling pathway. Conclusions: CHD4, which is highly expressed in cancer tissue, could be an independent prognostic factor for NSCLC patients. CHD4 plays an important role in regulating the proliferative and migratory abilities of NSCLC via likely the RhoA/ROCK pathway by regulating PHF5A.

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“…In GBM, PHF5A was discovered to be integral for the survival of GSCs by mediating the recognition of specific exons with unusual C‐rich 3’ splice sites in thousands of essential genes . Recently, using in vivo CRISPR screening, Zheng et al identified PHF5A as a key splicing factor involved in breast cancer progression; they found that PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A–SF3b complex modulated AS changes in apoptotic signaling pathways . However, there was no research investigating the role of PHF5A in lung cancer until a few months ago.…”

Section: Discussionmentioning

confidence: 99%

PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing

Mao

et al. 2019

Cancer Medicine

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Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)–finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer, but its biological function in lung cancer remains unclear. In the present study, we systematically analyzed the biological function and clinical relevance of PHF5A in non–small cell lung cancer (NSCLC). We found that PHF5A was significantly upregulated in NSCLC tumors compared with normal tissues in both TCGA data set and tissue microarrays. Upregulation of PHF5A was negatively correlated to the overall survival (OS) of lung adenocarcinoma (LUAD) patients. Loss‐of‐function and gain‐of‐function experiments confirmed that PHF5A functioned as an oncoprotein by promoting LUAD cell proliferation, migration and invasion, inducing G0/G1 cell cycle progression and inhibiting cisplatin–induced apoptosis. RNA–seq analysis identified many essential genes whose AS was dysregulated by PHF5A, including cell cycle–associated genes such as SKP2, CHEK2, ATR and apoptosis–associated genes such as API5 and BCL2L13. Additionally, pladienolide, a small molecular inhibitor of PHF5A, inhibited LUAD cell proliferation in a dose–dependent manner and induced AS changes similar to PHF5A knockdown. In conclusion, we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect.

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PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression

Cited by 69 publications

References 47 publications

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks

CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A

PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing

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