IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38968-7.html
   My bibliography  Save this article

Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas

Author

Listed:
  • Jiaxin Liang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Deyang Yu

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Chi Luo

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Parthenon Therapeutics)

  • Christopher Bennett

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Atavistik Bio)

  • Mark Jedrychowski

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Steve P. Gygi

    (Harvard Medical School)

  • Hans R. Widlund

    (Harvard Medical School)

  • Pere Puigserver

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression.

Suggested Citation

  • Jiaxin Liang & Deyang Yu & Chi Luo & Christopher Bennett & Mark Jedrychowski & Steve P. Gygi & Hans R. Widlund & Pere Puigserver, 2023. "Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38968-7
    DOI: 10.1038/s41467-023-38968-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38968-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38968-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Lin Song & Shi Tang & Xiaolei Han & Ziying Jiang & Lingling Dong & Cuicui Liu & Xiaoyan Liang & Jixin Dong & Chengxuan Qiu & Yongxiang Wang & Yifeng Du, 2019. "KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Georgina V. Long & Carina Fung & Alexander M. Menzies & Gulietta M. Pupo & Matteo S. Carlino & Jessica Hyman & Hamideh Shahheydari & Varsha Tembe & John F. Thompson & Robyn P. Saw & Julie Howle & Nich, 2014. "Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    3. Poulikos I. Poulikakos & Yogindra Persaud & Manickam Janakiraman & Xiangju Kong & Charles Ng & Gatien Moriceau & Hubing Shi & Mohammad Atefi & Bjoern Titz & May Tal Gabay & Maayan Salton & Kimberly B., 2011. "RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)," Nature, Nature, vol. 480(7377), pages 387-390, December.
    4. Ravid Straussman & Teppei Morikawa & Kevin Shee & Michal Barzily-Rokni & Zhi Rong Qian & Jinyan Du & Ashli Davis & Margaret M. Mongare & Joshua Gould & Dennie T. Frederick & Zachary A. Cooper & Paul B, 2012. "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion," Nature, Nature, vol. 487(7408), pages 500-504, July.
    5. Elena Piskounova & Michalis Agathocleous & Malea M. Murphy & Zeping Hu & Sara E. Huddlestun & Zhiyu Zhao & A. Marilyn Leitch & Timothy M. Johnson & Ralph J. DeBerardinis & Sean J. Morrison, 2015. "Oxidative stress inhibits distant metastasis by human melanoma cells," Nature, Nature, vol. 527(7577), pages 186-191, November.
    6. Timothy R. Wilson & Jane Fridlyand & Yibing Yan & Elicia Penuel & Luciana Burton & Emily Chan & Jing Peng & Eva Lin & Yulei Wang & Jeff Sosman & Antoni Ribas & Jiang Li & John Moffat & Daniel P. Suthe, 2012. "Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors," Nature, Nature, vol. 487(7408), pages 505-509, July.
    7. Zachary T. Schafer & Alexandra R. Grassian & Loling Song & Zhenyang Jiang & Zachary Gerhart-Hines & Hanna Y. Irie & Sizhen Gao & Pere Puigserver & Joan S. Brugge, 2009. "Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment," Nature, Nature, vol. 461(7260), pages 109-113, September.
    8. Chen Yang & Chengzhe Tian & Timothy E. Hoffman & Nicole K. Jacobsen & Sabrina L. Spencer, 2021. "Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    9. Ali Talebi & Jonas Dehairs & Florian Rambow & Aljosja Rogiers & David Nittner & Rita Derua & Frank Vanderhoydonc & Joao A. G. Duarte & Francesca Bosisio & Kathleen Eynde & Kris Nys & Mónica Vara Pérez, 2018. "Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Daniel E Carlin & Barry Demchak & Dexter Pratt & Eric Sage & Trey Ideker, 2017. "Network propagation in the cytoscape cyberinfrastructure," PLOS Computational Biology, Public Library of Science, vol. 13(10), pages 1-9, October.
    2. Vincent de Laat & Halit Topal & Xander Spotbeen & Ali Talebi & Jonas Dehairs & Jakub Idkowiak & Frank Vanderhoydonc & Tessa Ostyn & Peihua Zhao & Maarten Jacquemyn & Michele Wölk & Anna Sablina & Koen, 2024. "Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Yuelong Yan & Hongqi Teng & Qinglei Hang & Lavanya Kondiparthi & Guang Lei & Amber Horbath & Xiaoguang Liu & Chao Mao & Shiqi Wu & Li Zhuang & M. James You & Masha V. Poyurovsky & Li Ma & Kellen Olsze, 2023. "SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. C. Megan Young & Laurent Beziaud & Pierre Dessen & Angela Madurga Alonso & Albert Santamaria-Martínez & Joerg Huelsken, 2023. "Metabolic dependencies of metastasis-initiating cells in female breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Gholamreza Safaee Ardekani & Seyed Mehdi Jafarnejad & Larry Tan & Ardavan Saeedi & Gang Li, 2012. "The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-10, October.
    6. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Nicole Kiweler & Catherine Delbrouck & Vitaly I. Pozdeev & Laura Neises & Leticia Soriano-Baguet & Kim Eiden & Feng Xian & Mohaned Benzarti & Lara Haase & Eric Koncina & Maryse Schmoetten & Christian , 2022. "Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Anastasia Samarkina & Markus Kirolos Youssef & Paola Ostano & Soumitra Ghosh & Min Ma & Beatrice Tassone & Tatiana Proust & Giovanna Chiorino & Mitchell P. Levesque & Sandro Goruppi & Gian Paolo Dotto, 2023. "Androgen receptor is a determinant of melanoma targeted drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    9. Karl K. Krull & Syed Azmal Ali & Jeroen Krijgsveld, 2024. "Enhanced feature matching in single-cell proteomics characterizes IFN-γ response and co-existence of cell states," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Rongli Sun & Meng Cao & Juan Zhang & Wenwen Yang & Haiyan Wei & Xing Meng & Lihong Yin & Yuepu Pu, 2016. "Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice," IJERPH, MDPI, vol. 13(11), pages 1-11, October.
    11. Tal Levy & Kai Voeltzke & Laura Hruby & Khawla Alasad & Zuelal Bas & Marteinn Snaebjörnsson & Ran Marciano & Katerina Scharov & Mélanie Planque & Kim Vriens & Stefan Christen & Cornelius M. Funk & Chr, 2024. "mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    12. Ke Gong & Gao Guo & Nicole A. Beckley & Xiaoyao Yang & Yue Zhang & David E. Gerber & John D. Minna & Sandeep Burma & Dawen Zhao & Esra A. Akbay & Amyn A. Habib, 2021. "Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    13. Naomi Kawashima & Yuichi Ishikawa & Jeong Hui Kim & Yoko Ushijima & Akimi Akashi & Yohei Yamaguchi & Hikaru Hattori & Marie Nakashima & Seara Ikeno & Rika Kihara & Takahiro Nishiyama & Takanobu Morish, 2022. "Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38968-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.