MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

Yamashita, Nami; Morimoto, Yoshihiro; Fushimi, Atsushi; Ahmad, Rehan; Bhattacharya, Atrayee; Daimon, Tatsuaki; Haratake, Naoki; Inoue, Yuka; Ishikawa, Satoshi; Yamamoto, Masaaki; Hata, Tsuyoshi; Akiyoshi, Sayuri; Hu, Qiang; Liu, Tao; Withers, Henry G.; Liu, Song; Shapiro, Geoffrey I.; Yoshizumi, Tomoharu; Long, Mark D.; Küfe, Donald

doi:10.1158/1541-7786.mcr-22-0772

Cited by 21 publications

(29 citation statements)

References 65 publications

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“…The second, fourth, and fifth BDs of PBRM1 (BD2, BD4, and BD5, respectively) are most critical for the PBAF function by binding H3K14Ac (BD2 and BD5) and acetylated p53 (BD4), and as such, BD inhibitors have been developed for BD5 and BD2. ,,,, The functional role of the BD of BRD7 in PBAF is less defined. PBAF has recently been implicated in prostate and breast cancer progression through response to oxidative stress; however, the contribution of the BRD7 BD is yet to be addressed. , …”

Section: Discussionmentioning

confidence: 99%

“…PBAF has recently been implicated in prostate and breast cancer progression through response to oxidative stress; however, the contribution of the BRD7 BD is yet to be addressed. 36,59 Here, we report the discovery and validation of the first inhibitor with selectivity for BRD7. Using structure-based drug design, we adopted structural components of BRD7/9 ligands to identify a scaffold that can occupy the BRD7 binding pocket in a unique sterically restricted fashion.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Ordonez-Rubiano,

Maschinot,

Wang

et al. 2023

J. Med. Chem.

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Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Ordonez-Rubiano,

Maschinot,

Wang

et al. 2023

J. Med. Chem.

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show abstract

“…PBAF has recently been implicated in prostate and breast cancer progression through response to oxidative stress; however, the contribution of the BRD7 BD is yet to be addressed. 9,60 Here, we report the discovery and validation of the first BRD7-selective BD inhibitor. Using structure-based drug design, we adopted structural components of BRD7/9 ligands to identify a scaffold that can occupy the BRD7 binding pocket in a unique sterically-restricted fashion.…”

Section: Discussionmentioning

confidence: 99%

Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Ordonez

Maschinot²,

Wang

et al. 2023

Preprint

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Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromo-domain-containing protein 7 (BRD7) has been implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a se-ries of ligands designed to occupy this binding region and identified two BRD7-selective inhibitors, 1-78 and 2-77, that bind with nanomolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands oc-cupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

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“…The MUC1shRNA#2 (MISSION shRNA TRCN0000430218) and STAT1 shRNA (MISSION shRNA TRCN0000004266) were produced in HEK293T cells (RRID:CVCL_0063) as described previously ( 36 ). Flag-tagged MUC1-C/CD was inserted into the empty control pLenti CMV Blast DEST (706-1) vector (Plasmid #17451; Addgene) as described previously ( 27 ). Vector-transduced cells were selected for growth in 1–2 µg/mL puromycin.…”

Section: Methodsmentioning

confidence: 99%

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

Nakashoji,

Haratake,

Bhattacharya

et al. 2024

Cancer Research Communications

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The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCCs). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCCs). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and interferon (IFN) regulatory factors, and (iii) downstream IFN-stimulated genes (ISGs). MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by scRNA-seq analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression.

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MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

Cited by 21 publications

References 65 publications

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

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