A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dual-histone binding function

Mukherjee, Shravanti; Sen, Sabyasachi; Adhikary, Santanu; Sengupta, Aditi; Mandal, Pratiti; Dasgupta, Dipak; Chakrabarti, Partha; Roy, Siddhartha; Das, Chandrima

doi:10.1007/s12038-019-9980-5

Cited by 3 publications

(14 citation statements)

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“…It also recognizes H3K4me1/H3K14ac in DU154 and CWR22Rv1 prostate cancer cells [ 8 ], as well as H3K36me2/H4K16ac in SH-SY5Y neuroblastoma cells [ 4 , 9 ]. The dual recognition of two different histone modification by ZMYND8 suggests that the two separate conserved domains PWWP and BRD have different affinities towards their cognate histone binding partners [ 11 ]. When both H3K36me2 and H4K16ac exist in same histone octamer, the initial binding and recognition of the ZMYND8 to chromatin is considered through H3K36me2 because of its higher association rate, and the stability of the ZMYND8–nucleosome complex relies more on the binding to H4K16ac, due to its lower association rate [ 11 ].…”

Section: Characteristics and Functions Of Zmynd8mentioning

confidence: 99%

“…The function of ZMYND8 in cancer cells is mainly through modulation of histone methylation and acetylation [ 4 , 9 , 11 , 25 , 32 ]. It selectively recognizes H3K36me2/H4K16ac and regulates all-trans retinoic acid (ATRA)-responsive genes in SH-SY5Y neuroblastoma cells [ 4 ].…”

Section: Zmynd8 and Histone Modification In Cancer Cellsmentioning

confidence: 99%

“…It selectively recognizes H3K36me2/H4K16ac and regulates all-trans retinoic acid (ATRA)-responsive genes in SH-SY5Y neuroblastoma cells [ 4 ]. In MDA-MB-231 breast cancer cells, ZMYND8 is recruited to its target genes by binding to H3K36me2 and H4K16Ac ( Figure 3 A) [ 11 ]. Furthermore, in HeLa and MCF7 breast cancer cells, ATRA induces an H3K27me3 to H3K27ac switch and upregulates ZMYND8 expression [ 9 ].…”

Section: Zmynd8 and Histone Modification In Cancer Cellsmentioning

confidence: 99%

“…Differentiation of neuronal precursor cells induced by ATRA also requires transcriptional regulation, mediated by the ZMYND8–P-TEFb complex [ 13 ]. In MDA-MB-231 breast cancer cells, ZMYND8 upregulates differentiation genes and induces cellular differentiation [ 11 ]. The induction of breast cancer cell differentiation by ZMYND8 was noted through the H3K36me2/H4K16ac reader function of ZMYND8 [ 11 ].…”

Section: Tumor Suppression By Zmynd8mentioning

confidence: 99%

“…In MDA-MB-231 breast cancer cells, ZMYND8 upregulates differentiation genes and induces cellular differentiation [ 11 ]. The induction of breast cancer cell differentiation by ZMYND8 was noted through the H3K36me2/H4K16ac reader function of ZMYND8 [ 11 ]. Microarray analysis of breast cancer cells with ZMYND8 knockout by siRNA revealed that depletion of ZMYND8 reduces the expression of terminal differentiation markers, such as epithelial cell adhesion molecule (EPCAM) and cytokeratin 18 (CK18), by 80% and 86%, respectively [ 11 ].…”

Section: Tumor Suppression By Zmynd8mentioning

confidence: 99%

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Regulation of ZMYND8 to Treat Cancer

2021

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Zinc finger myeloid, nervy, and deformed epidermal autoregulatory factor 1-type containing 8 (Zinc finger MYND-type containing 8, ZMYND8) is a transcription factor, a histone H3-interacting protein, and a putative chromatin reader/effector that plays an essential role in regulating transcription during normal cellular growth. Mutations and altered expression of ZMYND8 are associated with the development and progression of cancer. Increased expression of ZMYND8 is linked to breast, prostate, colorectal, and cervical cancers. It exerts pro-oncogenic effects in breast and prostate cancers, and it promotes angiogenesis in zebrafish, as well as in breast and prostate cancers. In contrast, downregulation of ZMYND8 is also reported in breast, prostate, and nasopharyngeal cancers. ZMYND8 acts as a tumor suppressor in breast and prostate cancers, and it inhibits tumor growth by promoting differentiation; inhibiting proliferation, cell-cycle progression, invasiveness, and metastasis; and maintaining the epithelial phenotype in various types of cancers. These data together suggest that ZMYND8 is important in tumorigenesis; however, the existing data are contradictory. More studies are necessary to clarify the exact role of ZMYND8 in tumorigenesis. In the future, regulation of expression/activity of ZMYND8 and/or its binding partners may become useful in treating cancer.

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Section: Characteristics and Functions Of Zmynd8mentioning

confidence: 99%

Section: Zmynd8 and Histone Modification In Cancer Cellsmentioning

confidence: 99%

Section: Zmynd8 and Histone Modification In Cancer Cellsmentioning

confidence: 99%

Section: Tumor Suppression By Zmynd8mentioning

confidence: 99%

Section: Tumor Suppression By Zmynd8mentioning

confidence: 99%

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Regulation of ZMYND8 to Treat Cancer

2021

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ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation

et al. 2022

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Zinc Finger transcription factors are crucial in modulating various cellular processes, including differentiation. Chromatin reader Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8), an All-Trans Retinoic Acid (ATRA)-responsive gene, was previously shown to play a crucial role in promoting the expression of neuronal-lineage committed genes. Here, we report that ZMYND8 promotes neuronal differentiation by positively regulating canonical MAPT protein-coding gene isoform, a key player in the axonal development of neurons. Additionally, ZMYND8 modulates gene-isoform switching by epigenetically silencing key regulatory regions within the MAPT gene, thereby suppressing the expression of non-protein-coding isoforms such as MAPT213. Genetic deletion of ZMYND8 led to an increase in the MAPT213 that potentially suppressed the parental MAPT protein-coding transcript expression related to neuronal differentiation programs. In addition, ectopic expression of MAPT213 led to repression of MAPT protein-coding transcript. Similarly, ZMYND8-driven transcription regulation was also observed in other neuronal differentiation-promoting genes. Collectively our results elucidate a novel mechanism of ZMYND8-dependent transcription regulation of different neuronal lineage committing genes, including MAPT, to promote neural differentiation.

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Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition

Lin,

Sniezek,

McGann

et al. 2024

Preprint

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Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule drugs. To determine the mechanisms that drive these heterogeneous cellular responses, we quantified chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitor (HDACi) -treated cells derived from diverse genetic backgrounds. We utilized high-throughput sample multiplexed proteomics and integrated intelligent data acquisition methods to map proteomes of cancer cell lines in response to HDACi. We determined cell type-specific and ubiquitous cellular responses based on the quantification of 10,621 total proteins. We then established how coordinated remodeling of the proteome, transcriptome and chromatin state of HDACi treated cancer cells revealed convergent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) molecular phenotypes. HDACi- regulated proteins differ greatly across cell lines owing to heterogeneous molecular states of these cell lines. Finally, we demonstrated that HDACi treatment drove a highly cell-type specific response that may in part be explained by cell line-specific off-target drug engagement.

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A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dual-histone binding function

Cited by 3 publications

References 36 publications

Regulation of ZMYND8 to Treat Cancer

Regulation of ZMYND8 to Treat Cancer

ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation

Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition

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